AU3610499A - Novel substituted cyclic compounds, preparation method and pharmaceutical compositions containing them - Google Patents

Novel substituted cyclic compounds, preparation method and pharmaceutical compositions containing them Download PDF

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AU3610499A
AU3610499A AU36104/99A AU3610499A AU3610499A AU 3610499 A AU3610499 A AU 3610499A AU 36104/99 A AU36104/99 A AU 36104/99A AU 3610499 A AU3610499 A AU 3610499A AU 3610499 A AU3610499 A AU 3610499A
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ethyl
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substituted
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AU747301B2 (en
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Caroline Bennejean
Philippe Delagrange
Gerald Guillaumet
Frederique Klupsch
Michel Langlois
Daniel Lesieur
Pierre Renard
Marie-Claude Viaud
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Laboratoires Servier SAS
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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Abstract

The invention concerns compounds of formula (I): R-A-R' wherein: A is as defined in the description; R represents a group (V), (VI), (VII) or (VIII), where E, Q, R<SUP>1</SUP>, R<SUP>2</SUP>, R<SUP>3</SUP>, v and R<SUP>4 </SUP>are as defined in the description; R' represents a -(CH<SUB>2</SUB>)t-R<SUP>5 </SUP>group wherein t and R<SUP>5 </SUP>are as defined in the description.

Description

- 1 NEW SUBSTITUTED CYCLIC COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The present invention relates to new substituted cyclic compounds, to a process for their preparation and to pharmaceutical compositions containing them. 5 The prior art discloses retroamide chain indoles substituted by amides or carbamates for use as antagonists of GnRH (WO 9721707) and amide chain indoles substituted by amides, carbamates or ureas for use as antihypertensive agents (US 4803218). Retroamide chain benzofuran and benzothiophene compounds substituted by amides or carbamates have also been described as anti-inflammatory agents (EP 685475) or inhibitors of 10 bone resorption. The compounds of the present invention are new and have very valuable pharmacological characteristics in respect of melatoninergic receptors. In the last ten years, numerous studies have demonstrated the major role played by melatonin (5-methoxy-N-acetyltryptamine) in numerous physiopathological phenomena and also in the 15 control of circadian rhythm. Its half-life is, however, quite short owing to its being rapidly metabolised. It is thus very useful to be able to provide the clinician with melatonin analogues that are metabolically more stable and that have an agonist or antagonist character on the basis of which a therapeutic effect that is superior to that of the hormone itself may be expected. In addition to their beneficial action on disorders of circadian rhythm (J. Neurosurg. 1985, 63 20 pp 321-341) and sleep disorders (Psychopharmacology, 1990, 100, pp 222-226), ligands of the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp 222-223), and also for the treatment of Parkinson's disease (J. Neurosurg. 1985, 63, pp 321 25 341) and Alzheimer's disease (Brain Research, 1990, 528, pp 170-174). Those compounds have also shown activity on certain cancers (Melatonin - Clinical Perspectives, Oxford University Press, 1988, pp 164-165), ovulation (Science 1987, 227, pp 714-720), diabetes (Clinical -2 Endocrinology, 1986, 24, pp 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp 443-446). Those various effects take place via the intermediary of specific melatonin receptors. Molecular biology studies have shown the existence of a number of receptor sub-types that can bind the 5 hormone (Trends Pharmacol. Sci., 1995, 16, p 50; WO 97.04094). It has been possible to locate some of those receptors and to characterise them for different species, including mammals. In order to be able to understand the physiological functions of those receptors better, it is very valuable to have specific ligands available. Moreover, by interacting selectively with one or other of those receptors, such compounds can be excellent medicaments for the clinician in the 10 treatment of pathologies associated with the melatoninergic system, some of which have been mentioned above. In addition to the fact that the compounds of the present invention are new, they exhibit very great affinity for melatonin receptors and/or selectivity for one or other of the melatoninergic receptor sub-types. 15 More specifically, the present invention relates to compounds of formula (I): R-A-R' (I) wherein: + A represents: - a ring system of formula (II): 20 X wherein e X represents an oxygen, sulphur or nitrogen atom or a group C(H)q (wherein q is 0, 1 or 2) or NRI (wherein R represents a hydrogen atom, a linear or branched
(C,-C
6 )alkyl group, an aryl group, an aryl-(CI-C 6 )alkyl group in which the alkyl moiety is linear or branched, or SO 2 Ph), 25 * Y represents a nitrogen atom or a group C(H)q (wherein q is 0, 1 or 2), * Z represents a nitrogen atom or a group C(H)q (wherein q is 0, 1 or 2),
V
-3 but X, Y and Z cannot represent three hetero atoms simultaneously, * B represents a benzene or pyridine nucleus, * the symbol .. means that the bonds may be single or double, it being understood that the valency of the atoms is respected, 5 wherein R substitutes the ring B and R' substitutes the ring containing the groups X, Y and Z, or R and R' substitute the ring B, - a ring system of formula (III): wherein e X' represents an oxygen or sulphur atom or a group C(H)q (wherein q is 0, 1 10 or 2), * Y' represents a group C(H)q (wherein q is 0, 1 or 2) or NR1 wherein R is as defined hereinbefore, * Z' represents a group C(H)q (wherein q is 0, 1 or 2) or NR wherein R is as defined hereinbefore, 15 e T represents an oxygen or sulphur atom or a group C(H)q (wherein q is 0, 1 or 2), it being understood that, when Y' or Z' represents a hetero atom, the other three variables ((X', Z', T') and (X', Y', T'), respectively) cannot represent a hetero atom, e the symbol .. is as defined hereinbefore, 20 * B' represents: * a benzene nucleus, * a naphthalene nucleus when X', Y', Z' and T' do not simultaneously represent a group C(H)q (wherein q is 0, 1 or 2), * or a pyridine nucleus when X' and T' simultaneously 25 represent a group C(H)q (wherein q is 0, 1 or 2), 5'77 -4 wherein R substitutes the ring B' and R' substitutes the ring containing the groups X', Y', Z' and T', or R and R' substitute the ring B', - a ring system of formula (IV): (IV) D 5 representing the ring systems (IVa..): WW .. w W, - wW I (IN) (IVb) (Ic) (IVd) wherein . n is an integer such that 0 n 3, * W represents an oxygen, sulphur or nitrogen atom, or a group [C(H)q]p (wherein q is 0, 1 or 2, and p is 1 or 2) or NRO wherein R 0 is as defined 10 hereinbefore, " the symbol .... is as defined hereinbefore, wherein R' substitutes the ring 0 ) and R substitutes one or other of the two other rings, - or a biphenyl group wherein R substitutes one of the benzene rings and R' substitutes the 15 other, or R and R' substitute the same benzene ring, it being understood that the ring systems of formulae (II), (III) and (IV) and the biphenyl group may be unsubstituted or substituted (in addition to the substituents R and R') by from 1 to 6 radicals, which may be the same or different, selected from Ra, ORa, CORa, COORa, OCORa, OSO 2
CF
3 and halogen atoms, -5 wherein Ra represents a hydrogen atom, an unsubstituted or substituted linear or branched
(C
1
-C
6 )alkyl group, an unsubstituted or substituted linear or branched (C 2
-C
6 )alkenyl group, an unsubstituted or substituted linear or branched (C 2
-C
6 )alkynyl group, a linear or branched (C,-C 6 )polyhaloalkyl group, an unsubstituted or substituted (C 3 -C,)cycloalkyl 5 group, an unsubstituted or substituted (C 3 -C,)cycloalkyl-(C-C 6 )alkyl group in which the alkyl group is linear or branched, an unsubstituted or substituted (C 3 -C,)cycloalkenyl group, an unsubstituted or substituted (C 3
-C
8 )cycloalkenyl-(C-C 6 )alkyl group in which the alkyl group is linear or branched, an aryl group, an aryl-(C 1
-C
6 )alkyl group in which the alkyl moiety is linear or branched, an aryl-(C,-C 6 )alkenyl group in which the alkenyl 1o moiety is linear or branched, a heteroaryl group, a heteroaryl-(C-C 6 )alkyl group in which the alkyl moiety is linear or branched, a heteroaryl-(Cl-C 6 )alkenyl group in which the alkenyl moiety is linear or branched, an unsubstituted or substituted linear or branched
(C,-C
6 )heterocycloalkyl group, an unsubstituted or substituted heterocycloalkenyl group, a substituted or unsubstituted heterocycloalkyl-(Cl-C 6 )alkyl group in which the alkyl moiety 15 is linear or branched, or a substituted or unsubstituted heterocycloalkenyl-(Cl-C 6 )alkyl group in which the alkyl moiety is linear or branched, + R represents : - a group of formula (V): -C -R' I| (V) Q 20 wherein 9 Q represents a sulphur or oxygen atom, * R' represents a group NR'aR"a or OR'a (wherein R'a and R"a, which may be the same or different, may take any of the values of Ra and may also form, together with the nitrogen atom carrying them, a 5- to 10-membered cyclic group which may contain, in addition to the nitrogen atom by which it is linked, from one to 25 three hetero atoms selected from oxygen, sulphur and nitrogen, and R'a may take any of the values of Ra except for the hydrogen atom), - a group of formula (VI): -6 R2 -N R (VI) ' wherein * R 2 represents a group Ra as defined hereinbefore, e R' represents a group COR'a, CSR'a, CONR'aR"a, CSNR'aR",a, COOR'a, CSOR'a or S(O)vR'a (wherein R'a and R"a, which may be the same or different, are as defined 5 hereinbefore and may also form, together with the nitrogen atom carrying them, a cyclic group as defined hereinbefore, and v is 1 or 2), - a group of formula (VII) : -S-R (VII) (O), wherein v is as defined hereinbefore and R represents a group NR'aR"a, NRaCOR'a, 10 NRaCSR'a, NRaCONR'aR"a, NRaCSNR'aR"a or NRaCOOR'a, wherein Ra, R'a and R"a are as defined hereinbefore, - or, when A represents a ring system of formula (II) or (III) or a biphenyl group, forms, together with two adjacent carbon atoms of the ring structure A carrying it, a ring of formula (VIII): (VIII) A 15 (O), (O), Q Ra Ra I I II I whereinErepresentsagroup -S-N- ,-S-N-C- -N-S- -N-C I ( )1 Ra Ra (O)v Q -7 Ra Ra R'a R'a I I I I -N-C-0- , -N-C-N-, -C-N- or -C-0-whereinr,Q,Ra,R'a II II II I I Q Q Q Q and v are as defined hereinbefore, the ring formed containing from 5 to 7 atoms and it being possible for the said ring to contain 5 from 1 to 3 hetero atoms selected from nitrogen, sulphur and oxygen, and one or more unsaturations, and being optionally substituted by one or more radicals, which may be the same or different, selected from Ra, ORa, CORa, COOR., OCORa, NR'aR!'a, NRaCOR'a, CONR'aR"a, cyano, oxo, SRa, S(O)Ra, S0 2 Ra, CSRa, NRaCSR'a, CSNR'aR"a, NRaCONR'aR"a' NRaCSNR'aR"a and halogen atoms, 10 wherein Ra, R'a and R"a, which may be the same or different, are as defined hereinbefore and R'a and R"a may also form, together with the nitrogen atom carrying them, a cyclic group as defined hereinbefore, * and R' represents a group of formula (IX): -G-R' (IX) 15 wherein e G represents an alkylene chain -(CH 2 )c- (wherein t is an integer such that 0 t 4 when A represents a tricyclic structure and such that 1 t s 4 when A represents a bicyclic structure), optionally substituted by one or more radicals, which may be the same or different, selected from Ra, ORa, COORa, CORa (in which R is as defined hereinbefore) or halogen atoms, R R I a I a and R 5 represents a group -- N--R'a -N-C-NR'aR!a , -- -NR'aRa R QQ I wariQR3 R nR or -O-N-C-R' wherein Q, Ra, Ra and R'a (which may be the same or different) ||I a 20 are as defined hereinbefore, it being possible for R'a and R". to form, together with the nitrogen atom carrying them, a cyclic group as defined hereinbefore, it being understood that: -8 - "heterocycloalkyl" is taken to mean any saturated mono- or poly-cyclic group containing from 5 to 10 atoms containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur, - "heterocycloalkenyl" is taken to mean any non-aromatic mono- or poly-cyclic group 5 containing one or more unsaturations, containing from 5 to 10 atoms and which may contain from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur, - the term "substituted" used in respect of the expressions "alkyl", "alkenyl" and "alkynyl" indicates that the groups in question are substituted by one or more radicals, which may be the same or different, selected from hydroxy, linear or branched 10 (C 1
-C
6 )alkoxy, linear or branched (C 1
-C
6 )alkyl, linear or branched (Cl-C 6 )polyhaloalkyl, amino and halogen atoms, - the term "substituted" used in respect of the expressions "cycloalkyl", "cycloalkylalkyl", "cycloalkenyl", "cycloalkenylalkyl", "heterocycloalkyl", "heterocycloalkenyl", "hetero cycloalkylalkyl" and "heterocycloalkenylalkyl" indicates that the cyclic moiety of the 15 groups in question is substituted by one or more radicals, which may be the same or different, selected from hydroxy, linear or branched (C,-C 6 )alkoxy, linear or branched
(C,-C
6 )alkyl, linear or branched (C-C)polyhaloalkyl, amino and halogen atoms, - "aryl" is taken to mean any aromatic, mono- or poly-cyclic group containing from 6 to 22 carbon atoms, and also the biphenyl group, 20 - "heteroaryl" is taken to mean any aromatic mono- or poly-cyclic group containing from 5 to 10 atoms containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur, it being possible for the "aryl" and "heteroaryl" groups to be substituted by one or more radicals, which may be the same or different, selected from hydroxy, linear or branched -9 (Cl-C 6 )alkoxy, linear or branched (C,-C 6 )alkyl, linear or branched (C 1
-C
6 )polyhaloalkyl, cyano, carboxy, nitro, amino and halogen atoms, it being understood that : - when A represents an indole nucleus, there cannot be any substituents in the 2-position, 5 - when A represents an indole nucleus and R represents a group -NHCOR'a, -NHCOOR'a or NHCONR'aR"a, then G-R cannot represent a group -(CH 2
)
2 -NHCORb wherein Rb represents a (C,-C 4 )alkyl or CF 3 group, - when A represents a benzofuran or benzothiophene nucleus, there cannot be any COPh groups (wherein Ph is substituted or unsubstituted) in the 2-position, 10 - when A represents a benzofuran or benzothiophene nucleus, R cannot represent a group -NRaCOR, -NHSO 2 Rc, -NHCOCH 2 Rc or NHCONHRc wherein Rc represents a heterocyclic or aryl group, - when A represents a tetrahydronaphthalene group, R 5 cannot represent a group CONR'aR"a' 15 - when A represents a hydrocarbon ring system and R represents a group NHCOR'a, then R cannot represent a group COOR'a, - the compound of formula (I) cannot represent: * N-{8-[(acetylamino)methyl]-2-naphthyl}-2-methylpropanamide, 9 N-(2-{5-[(4-ethoxyanilino)sulphonyl]-1H-indol-3-yl}ethyl)acetamide, 20 e 8-[(acetylamino)methyl]-N-isopropyl-2-naphthamide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. Among the pharmaceutically acceptable acids there may mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, 25 trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid etc.. 'T R -10 Among the pharmaceutically acceptable bases there may mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.. Preferred compounds of the invention are those wherein A represents a ring system 4 S3 of formula (II') B (II') wherein B, X and the symbol are as defined 5 hereinbefore, 8 7 or (III'): B' wherein B', T', X' and the symbol .... are as defined 6 5 x 3 hereinbefore. The invention advantageously relates to compounds wherein A (unsubstituted or substituted by a single substituent (in addition to R and R') preferably in the 2-position (formula II') or in the 3 10 position (formula III'), 4 5 3 represents a cyclic system of formula (II'): B wherein B, X and the symbol 7 are as defined hereinbefore, such as, for example, (dihydro)benzothiophene, (dihydro)benzofuran, indole, indoline, indan, indene, azaindole, thienopyridine or furopyridine, or of formula (III'): wherein B', T', X' and the symbol .... are as defined 5 4 15 hereinbefore, such as, for example, naphthalene, tetrahydronaphthalene, (thio)chroman, (dihydro)benzodioxin, (dihydro)benzoxathiin, (dihydro)benzochromene. Even more advantageously, the invention relates to compounds wherein A of formula (II') or (III') is substituted by R in the 5-position (formula II') or 7-position (formula III') and by R' in the 3-position (formula II') or 1- or 2-position (formula III').
- 11 Preferred substituents R of the invention are those represented by a group of formula (V), (VI) or (VII). More advantageously, preferred substituents R of the invention are those represented by a group of formula (V) wherein Q represents an oxygen atom and R' represents a group NR'aR"a (wherein 5 R'a and R"a are as defined hereinbefore) or OR'a (wherein Ra is as defined hereinbefore), a group of formula (VI) wherein R 3 represents a group COR'a or COOR'a (wherein R'a is as defined hereinbefore), or a group of formula (VII) wherein v is 2 and RW represents a group NR'aR"a as defined hereinbefore. 10 Even more advantageously, preferred substituents R of the invention are those represented by a group CONR'aR". or SO 2 NR'aR"a wherein R'a and R"a, which may be the same or different, represent a hydrogen atom or an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 15 isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, or form, together with the nitrogen atom carrying them, a piperazine, piperidine, morpholine or thiomorpholine group, or by a group NCOR'a, NCOOR'a or COOR'a wherein R'a represents a hydrogen atom, an alkyl, 20 polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, and R'a represents an alkyl, 25 polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl.
- 12 Preferred substituents R' of the invention are those wherein G represents an unsubstituted or substituted alkylene chain -(CH 2 )c-, wherein t is 2 or 3, and R represents a group Ra Ra -N-C-R'a , -N-C-NR'aR"a or -C-NRaR'a , whereinRa, Ra, R"a and Q are as defined hereinbefore. 5 Even more advantageously, preferred substituents R' of the invention are those wherein G represents a group -(CH 2
)
1 -, wherein t is 2 or 3, and R' represents a group - NHC - R'a , wherein R'a represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert 10 butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, or G represents a group -(CH 2
)
3 - and R 5 represents a group - C - NHRa , wherein Ra II represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, 15 cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl. 20 More especially, preferred compounds of the invention are those wherein A represents a ring system of formula (II') or (III') and R represents a group of formula (V), (VI) or (VII). More advantageously, the invention relates to compounds wherein : A represents a group of formula (II') or (III') substituted in the 5-position (formula II') or 7 position (formula III') by R and in the 3-position (formula II') or 1- or 2-position (formula III') by
R',
- 13 and R represents a group CONR'aR"a, SO 2 NR'aR"a, COOR',a, NHCOR'a or NHCOOR'a (wherein R'a, R"a and R'a are as defined hereinbefore). Even more advantageously, preferred compounds of the invention are those wherein A represents a ring system of formula (II') or (III') optionally substituted (in addition to R and R') by a 5 substituent in the 2-position (formula II') or 3-position (formula III'), substituted in the 5-position (formula II') or 7-position (formula III') by R and in the 3-position (formula II') or 1- or 2-position (formula III') by R', R represents a group CONR'aR"a, SO 2 NR'aR"a, COORa, NHCOR'a or NHCOOR'a (wherein R'a, R"a and R'a are as defined hereinbefore), 10 and R' is such that G represents an unsubstituted or substituted alkylene chain -(CH 2 ),-, wherein Ra Ra t is 2 or 3, and R 5 represents a group -N-C-R'a , -N-C-NR'aR"a or -C-NR'aR"a, I I || || Q Q Q wherein Ra, R'a, R"a and Q are as defined hereinbefore. Even more especially, the invention relates to (dihydro)benzothiophenes, (dihydro)benzofurans, indoles, indolines, indenes, indans, azaindoles, thieno- or furopyridines optionally substituted in 15 the 2-position, and to dihydronaphthalenes, tetrahydronaphthalenes, naphthalenes or chromans optionally substituted in the 3-position, substituted in the 5-position (or 7-position, respectively) by a group CONR'aR", SO2NR'aR"a, COOR'a, NHCOR'a or NHCOOR'a wherein R'a and R"a, which may be the same or different, represent a hydrogen atom, an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, 20 cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, or R'a and R"a form, 25 together with the nitrogen atom carrying them, a piperazine, piperidine, morpholine or thiomorpholine group, and R'a represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- -14 butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, and substituted in the 3-position (or 1- or 2-position, respectively) by a group -(CH 2 ),-NHCOR'a 5 wherein t is 2 or 3 and R', represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, 10 ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl. Even more advantageously, preferred compounds of the invention are: naphthalenes, dihydronaphthalenes or tetrahydronaphthalenes optionally substituted in the 3 postion, substituted in the 7-position by a group NHCOR,, NHCOORa, CONHRa or COOR'a (wherein Ra and R'a are as defined hereinbefore) and substituted in the 1-position by a group 15 -(CH 2 ),-NHCOR'a wherein t is 2 or 3 and R'a is as defined hereinbefore, or benzofurans or benzothiophenes optionally substituted in the 2-position, substituted in the 5 position by a group NHCORa, NHCOORa, CONHRa or COOR'a (wherein Ra and Ria are as defined hereinbefore) and substituted in the 3-position by a group -(CH 2 )t-NHCOR'a wherein t is 2 or 3 and R'a is as defined hereinbefore. 20 The invention relates very particularly to the compounds of formula (I) that are: - N-{2-[6-(acetylamino)-2,3-dihydro-1H-1-indenyl]ethyl}acetamide, - methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate, - methyl 3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate, - methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate, 25 - methyl 3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate, - NN-diphenyl-3-[3-(acetylamino)propyl]benzo[b]furan-5-carboxamide, - 3-[2-(acetylamino)ethyl]-1-benzofuran-5-carboxamide, - 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxamide, - 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxamide, I7 - 15 - 3- {2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-i -benzofuran-5-carboxamide, - 3-[2-(acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide, - 3- {2-[(cyclopentylcarbonyl)amino]ethyl} -N-methyl-i -benzofuran-5-carboxamide, - 3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide, 5 - 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide, - 3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide, - 3-[2-(acetylamino)ethyl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, - N-isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b]thiophene-5 carboxamide, 10 - N- {3-[2-(acetylamino)ethyl]- 1 -benzofuran-5-yl} -2,2,2-trifluoroacetamide, - N-{2-[5-(acetylamino)-1-benzofuran-3-yl]ethyl}cyclopropanecarboxamide, - N-{2-[5-(acetylamino)-1-benzothiophen-3-yl]ethyl}benzamide, - N-{8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}butanamide, - N-(8- {2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)- 1 -cyclohexanecarboxamide, 15 - N-{8-[2-(heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide, - N-{8-[2-(acetylamino)ethyl]-2-naphthyl}acetamide, - N-ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide, - NN-diethyl-8-{2-[2-[(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide, - N-phenyl-8-(2-{methyl[(propylamino)carbonyl]amino}ethyl)-2-naphthamide, 20 - N-benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide, - N-(2-{7-[(methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide, - N-{2-[7-(aminosulphonyl)-1-naphthyl]ethyl}acetamide, - N-(2- {7-[(methylamino)sulphonyl]- 1 -naphthyl}ethyl)acetamide, - N-(2- {7-[(methylamino)sulphonyl]- 1 -naphthyl} ethyl)-2-furamide, 25 - N-(2-{7-[(ethylamino)sulphonyl]- 1 -naphthyl} ethyl)benzamide, - N-(2- {7-[(methylamino)sulphonyl]- 1 -naphthyl}ethyl)cyclopropanecarboxamide, - N-(3- {5-[(methylamino)sulphonyl]- 1 -benzofuran-3-yl}propyl)acetamide, - N-(2-{5-[(propylamino)sulphonyl]- 1 -benzofuran-3-yl}ethyl)acetamide, - N-(2- {5-[(cyclopropylamino)sulphonyl]- 1 -benzofuran-3-yl}ethyl)benzamide, 30 - N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-2-firamide, - N-(2- {5-[(methylamino)sulphonyl]- 1 -benzofuran-3-yl} ethyl)cyclopropanecarboxamide, - N-(2-{2-benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)acetamide, -16 - N-(2-{5-[(isopropylamino)sulphonyl]-1 -benzothiophen-3-yl}ethyl)cyclopropane carboxamide, - N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[ 2 ,3-b]pyridin-3-yl}ethyl)acetamide, - N-(2-(5-[(methylamino)sulphonyl]-1H-pyrrolo[ 2 ,3-b]pyridin-3-yl}ethyl)cyclopropane 5 carboxamide, - N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[ 2 ,3-b]pyridin-3-yl}ethyl)benzamide, - N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[ 2 ,3-b]pyridin-3-yl}ethyl)-2-furamide, - methyl N-{3-[2-(acetylamino)ethyl]benzo[b]furan-5-yl}carbamate, - methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate, 10 - tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate, - tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate, - methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate, - methyl 3-[2-(isobutyrylamino)ethyl]-1-benzofuran-5-yl-carbamate, - methyl 5-[(acetylamino)methyl]-2,3-dihydro-1,4-benzodioxin-6-yl-carbamate, 15 - methyl 3-[(acetylamino)methyl]-3,4-dihydro-2H-chromen-6-yl-carbamate, - ethyl 3-[2-(acetylamino)ethyl]-2,3-dihydro-1H-inden-5-yl-carbamate, - methyl 3-[2-(acetylamino)ethyl]-1H-pyrrolo[ 2 ,3-b]pyridin-5-yl-carbamate, - methyl 3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[ 2 ,3-b]pyridin-5-yl-carbamate, - methyl 3-[2-(benzoylamino)ethyl]-1H-pyrrolo[ 2 ,3-b]pyridin-5-yl-carbamate, 20 - methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate, - ethyl N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate, - methyl N- {8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl }carbamate, - hexyl N- {8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl} carbamate, - methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate, 25 - methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate, - methyl 3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate, - methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate, - methyl 3-[2-(isobutylamino)ethyl]-1-benzofuran-5-carboxylate, - 3-[2-(benzoylamino)ethyl]- 1 -benzofuran-5-carboxamide.
-17 The enantiomers and diastereoisomers, as well as the addition salts with a pharmaceutically acceptable acid or base, of the preferred compounds of the invention form an integral part of the invention. The invention relates also to a process for the preparation of compounds of formula (I), which 5 process is characterised in that there is used as starting material the compound of formula (X):
H
3 C- 0 ( X A-R' wherein A and R' are as defined hereinbefore, which is subjected to demethylation using conventional agents such as HBr, AlCl 3 , AlBr 3 , BBr 3 or Lewis acid/nucleophile binary systems such as AlCl 3 /PhCH 2 SH, or BBr 3 /Me 2 S, for example, to obtain the compound of formula (XI): HO-A-R' (XI) 10 wherein A and R' are as defined hereinbefore, + which is converted, by means of the action of reagents such as POCl 3 , PCl 5 , Ph 3 PBr 2 , PhPCl 4 , HBr or HI, into the corresponding halogenated compound of formula (XII): Hal-A-R' (XII) 5 wherein A and R' are as defined hereinbefore and Hal represents a halogen atom (which compounds of formula (XII) can be obtained by exchange reactions such as, for example, the treatment of a chlorinated compound with KF in dimethylformamide to yield the corresponding fluorinated compound or the treatment of a brominated compound with KI in the presence of copper salts to yield the corresponding iodinated compound), 20 which is treated : with carbon monoxide and Bu 3 SnH, the reaction being catalysed with palladium(O), to yield the corresponding aldehyde of formula (XIII): - 18 H-C-A-R' (XIII) 11 0 wherein A and R' are as defined hereinbefore, which compound of formula (XIII) may alternatively be obtained by customary lithiation methods starting from the halogenated compound of formula (XII), or via the corresponding 5 vinyl compound (obtained starting from the compound of formula (XII) by the action of vinyltributyltin and tetrakis palladium) subjected to ozonolysis, or furthermore by direct formylation of the nucleus A, for example according to a Vilsmeier reaction, which compound of formula (XIII) is subjected to an oxidising agent to obtain the compound of formula (XIV): HOOC-A-R (XIV) 10 wherein A and R' are as defined hereinbefore, which is: * either subjected, in the presence of an acid catalyst, to the action of an alcohol of formula
R'
1 ,0H, wherein R% is as defined hereinbefore, to yield the compound of formula (I/a), a 15 particular case of the compounds of formula (I) : Ri - O - C - A - R' (I/a) aII 0 wherein A, R. and R' are as defined hereinbefore, which may be subjected to a thionating agent, such as Lawesson's reagent, for example, to yield the compound of formula (I/b), a particular case of the compounds of formula (I): Ra - 0 - C - A - R' (I/b) a 1 S 20 wherein A, Ra and R' are as defined hereinbefore, * or converted, after the action of thionyl chloride and an azide, and then of an acid, into the pound of formula (XV): -19
H
2 N -A-R' (XV) wherein A and R' are as defined hereinbefore, with which there is condensed: - either an acyl chloride CICORa or the corresponding anhydride (mixed or symmetrical), wherein R. is as defined hereinbefore, to yield the compound of formula (I/c), a particular 5 case of the compounds of formula (I) : Ra--C -NH- A -R' (I/c) 0 wherein Ra, A and R' are as defined hereinbefore, which may be subjected to the action of a compound of formula (XVI): RIa--J (XVI) wherein R'a is as defined hereinbefore and J represents a leaving group such as a halogen atom or 10 a tosyl group, to obtain the compound of formula (Id), a particular case of the compounds of formula ( I): RI Ra-C-N-A-R (I/d) I I 0 wherein Ra, R'a, A and R' are as defined hereinbefore, which compounds of formulae (I/c) and (I/d) constitute the compound of formula (I/e), a 15 particular case of the compounds of formula (I): -20 Ra Ra -C -N- A -R' (1le) 0 wherein Ra, R'a, A and R' are as defined hereinbefore, which compound of formula (I/e) may be subjected to a thionating agent, such as Lawesson's reagent, for example, to obtain the compound of formula (I/f), a particular case of the compounds 5 of formula (I): -R' Ra -C-N -A-R' (/) I| S wherein Ra, R'a, A and R' are as defined hereinbefore, - or a compound of formula (XVII): Q=C=N-R'a (XVII) 10 wherein Q and R'a are as defined hereinbefore, to yield the compound of formula (I/g), a particular case of the compounds of formula (I): R'NHC-NH--A-R' (/g) Q wherein R'a, Q, A and R' are as defined hereinbefore, 15 which may be subjected to the action of a compound of formula (XVI) to obtain the compound of formula (I/h), a particular case of the compounds of formula (I): 77 -21 Ra RR' N-C -N-A-R' (I/h) I I Q wherein Q, R'a, A and R' are as defined hereinbefore and R 2 a and R' 2 a, which may be the same or different, may take any of the values of Ra except for the hydrogen atom and cannot form a cyclic structure together with the nitrogen atom carrying them, 5 - or a compound of formula (XVIII) : R'a - -C -Cl (XVIII) wherein R'a is as defined hereinbefore, or its corresponding anhydride (R'aOCO) 2 0, to obtain the compound of formula (I/i), a particular case of the compounds of formula (I): R'aOC-NH-A-R' (I/i) 10 wherein R'a, A et R' are as defined hereinbefore, which may be subjected to the action of a compound of formula (XVI) and/or the action of a thionating agent to yield the compound of formula (I/j), a particular case of the compounds of formula (I): Ra R'aO-C-N-A-R' (I/j) Q 15 wherein Ra, R'a, Q, A and R' are as defined hereinbefore, - or a compound of formula (XIX) : RaSO 2 Cl (XIX) - 22 wherein R, is as defined hereinbefore, optionally followed by the action of a compound of formula (XVI) to yield the compound of formula (I/k), a particular case of the compounds of formula (I): R' a RaSO 7 -N-A-R' (I/k) wherein Ra, A and R' are as defined hereinbefore, + or which compound of formula (XI) is converted, by means of the action of benzylthiol and trifluoromethanesulphonic acid, into the corresponding benzylthio compound of formula (XX): 10 Ph-CH 2 -S-A-R' (XX) wherein A and R' are as defined hereinbefore, which is placed in the presence of iodosobenzene and hydrochloric acid to yield the compound of formula (XXI) :
CISO
2 -A-R' (XXI) 11s wherein A and R' are as defined hereinbefore, with which there is condensed an amine R'aR"aNH (wherein R'a and R"a are as defined hereinbefore), to obtain the compound of formula (I/1), a particular case of the compounds of formula (I): R'aR".NS2-A-R' (I/l) 20 wherein R'a, R"a, A and R' are as defined hereinbefore, it being possible for the compound of formula (I/la), a particular case of the compounds of formula (I/1): -23
H
2
NSO
2 -A-R' (I/la) wherein A and R' are as defined hereinbefore, to be subjected to the action e of an acyl chloride ClCOR'a, optionally followed by the action of a compound of formula (XVI) and/or Lawesson's reagent, 5 to yield the compound of formula (I/m), a particular case of the compounds of formula (I): R I a R'aC-N-SOi-A-R' (I/m) al Q wherein Ra, R'a, Q, A and R' are as defined hereinbefore, e of a compound of formula (XVII), optionally followed by the action of a compound of formula (XVI) to obtain the compound of formula (I/n), a particular case of the compounds of formula (I) Ra RaRaN-C-N-SO 2-A-R' (I/n) II 10Q wherein Ra, R'a, R"a, Q, A and R' are as defined hereinbefore, e or of a compound of formula (XVIII), optionally followed by the action of a compound of formula (XVI), to yield the compound of formula (I/o), a particular case of the compounds of formula (I): R Ia R'aOC-N-SO -A-R' (I/o) II 15 0 wherein Ra, R'a, A and R' are as defined hereinbefore, -24 which compounds (I/a) to (I/o) can be purified in accordance with a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and, optionally, are separated into their isomers in accordance with a conventional separation technique. 5 The starting compounds (X) are either commercially available or are described in the literature, for example in the Patent Applications EP0447285, EP0527687, EP0562956, EP0591057, EP0662471, EP0745586, EP0709371, EP0745583, EP0721938, EP0745584, EP0737670, EP0737685, or W09738682. Another advantageous process of the invention relating to preparation of the compounds of 10 formula (I) is characterised in that there is used as starting material the compound of formula (XXII): R 0 Y"l Y 11 (X X II) wherein R and the symbol ... are as defined hereinbefore, Y" represents a group C(H)q (wherein q is 0, 1 or 2) or a bond, and X" represents an oxygen, nitrogen or sulphur atom or a group C(H)q 15 (wherein q is 0, 1 or 2) or NR1 (wherein R is as defined hereinbefore), it being understood that when X" represents a nitrogen atom or a group NR then Y" represents a bond, which is subjected to a Wittig reaction and then to reduction to yield the compound of formula (XXIII): R G-CN (XXIII) X11. 20 wherein R, X", Y", G and the symbol .are as defined hereinbefore, which may be oxidised to yield the compound of formula (XXIV): -25 R G-CN (XXIV) X." wherein R', X", Y", G and the symbol .are as defined hereinbefore, which is : * either hydrolysed in an acid or basic medium and then subjected, after activation to the acid 5 chloride form or in the presence of a coupling agent, to the action of an amine HNR'aR"a wherein R'a and R"a are as defined hereinbefore to yield the compound of formula (I/p), a particular case of the compounds of formula (I): 0 G J NR'aR"a (I/p) X., wherein R, X", Y", G, R'a, R"a and the symbol .are as defined hereinbefore, 10 which may be subjected to a thionating agent such as Lawesson's reagent to yield the compound of formula (I/q), a particular case of the compounds of formula (I): S R G J, NR'aR"a 'Y" (I/q) X" wherein R, X", Y", G, R'a, R"a and the symbol .are as defined hereinbefore, * or hydrolysed in an acid or basic medium and then converted into the corresponding azide to 15 yield, after having been subjected to a Curtius rearrangement and hydrolysis, the compound of formula (XXV): S" -1" -26 R
G-NH
2 Y" (XXV) XI wherein R, X", Y" and G are as defined hereinbefore, which is reacted with: 5 - an acyl chloride CICOR'a or the corresponding anhydride (mixed or symmetrical) wherein R'a is as defined hereinbefore, optionally followed by the action of a compound of formula (XVI) and/or the action of a thionating agent to yield the compound of formula (I/r), a particular case of the compounds of formula (I): R I a G-N-C-R' R I (I/r) X"1 10 wherein R, X", Y", G, Ra, R'a, Q and the symbol .. are as defined hereinbefore, - or with a compound of formula (XVII), optionally followed by the action of a compound of formula (XVI) to yield the compound of formula (I/s), a particular case of the compounds of formula (I): R I a G-N-C-NR'aR"a R I (I/s) X"1 5 wherein R, X", Y", G, Ra, R'a, R"a, Q and the symbol .. are as defined hereinbefore, which compounds (I/p) to (I/s) can be purified in accordance with a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and, optionally, are separated into their isomers in accordance with a conventional separation technique.
-27 The compounds of formula (XXII) are either commercially available or easily accessible to the person skilled in the art, * starting from the compound of formula (XXVI): R X'" Me (XXVI) 5 wherein R is as defined hereinbefore and X"' represents an oxygen or sulphur atom or a group NRO (wherein R 0 is as defined hereinbefore), (the compound of formula (XXVI) either being commercially available or being obtained starting from the compound of formula (XXVI') : 0 (XXVI') X"' Me 10 wherein X.' is as defined hereinbefore, by conventional reactions for substitution of the aromatic nucleus), which is subjected to the action of AlCl 3 to yield the compound of formula (XXVII): 0 R Me (XXVII) X"'H wherein R and X' are as defined hereinbefore, 15 which is subjected to bromination to obtain the compound of formula (XXVIII): - 28 0 R Br (XXVIII) X'H wherein X'" and R are as defined hereinbefore, which is placed in a basic medium to yield the compound of formula (XXIX), a particular case of the compounds of formula (XXII): R 0 (XXIX) 5 wherein R and X"' are as defined hereinbefore, or starting from the compound of formula (XXX): R -COOH (XXX) wherein R, X", Y" and the symbol .... are as defined hereinbefore, 10 which is cyclised in the presence of polyphosphoric acid to yield the compound of formula (XXII). The invention relates also to a process for the preparation of compounds of formula (I) wherein R represents a ring of formula (VIII), which process is characterised in that compounds of formulae (I/a) to (I/s) are used as starting materials, which are cyclised according to methods described in 15 the literature, for example in the Patent Applications EP0708099 or W09732871. The compounds of the invention and pharmaceutical compositions comprising them are proving to be useful in the treatment of disorders of the melatoninergic system.
-29 Pharmacological study of the compounds of the invention has in fact shown them to be non toxic, to have strong affinity for melatonin receptors and to possess important activities in respect of the central nervous system and, in particular, there have been found therapeutic properties in relation to sleep disorders, anxiolytic, antipsychotic and analgesic properties and in relation to 5 the microcirculation, enabling it to be established that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal affective disorder, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue resulting from jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders associated 10 with normal or pathological ageing, migraine, memory loss, Alzheimer's disease, and also cerebral circulation disorders. In another field of activity, it appears that, in treatment, the products of the invention can be used in sexual dysfunction, that they have ovulation-inhibiting properties and immunomodulating properties and are able to be used in the treatment of cancers. The compounds will preferably be used in the treatment of seasonal affective disorder, sleep 15 disorders, cardiovascular pathologies, insomnia and fatigue resulting from jet lag, appetite disorders and obesity. For example, the compounds will be used in the treatment of seasonal affective disorder and sleep disorders. The present invention relates also to pharmaceutical compositions comprising at least one 20 compound of formula (I), alone or in combination with one or more pharmaceutically acceptable excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets, dragdes, sublingual tablets, 25 sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.
T
-30 The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possible associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in 1 or more administrations. The following Examples illustrate the invention but do not limit it in any way. The following 5 Preparations yield compounds of the invention or synthesis intermediates that are useful in preparation of the compounds of the invention. Preparation 1: N-[2-(7-Hydroxy-1-naphthyl)ethylacetamide Under an inert atmosphere, 27.5 mmol of boron tribromide/dimethyl sulphide complex are dissolved in 100 ml of dichloromethane and stirred for 15 min at ambient temperature. A 10 solution of 13.7 mmol of N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide in 50 ml of dichloromethane is added and the reaction mixture is heated at reflux for 30 hours. After cooling, the reaction mixture is hydrolysed with caution and the dichloromethane is evaporated off. The mixture is then extracted with ethyl acetate, the combined organic phases are washed with a IM aqueous solution of potassium bicarbonate and then with 1M sodium hydroxide solution. The 15 organic phase is dried over magnesium sulphate and concentrated to yield the title compound. Preparation 2: N-[2-(7-Hydroxy-1-naphthyl)ethyll-2-phenylacetamide The procedure is as in Preparation 1, but the N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide is replaced by N-[2-(7-methoxy- 1 -naphthyl)ethyl]-2-phenylacetamide. In Preparations 3 to 37, the procedure is as in Preparation 1, but the N-[2-(7-methoxy-l 20 naphthyl)ethyl]acetamide is replaced by the appropriate methoxylated starting substrate. Preparation 3 : N-[2-(7-Hydroxy-1-naphthyl)ethyll-2-bromoacetamide Preparation 4 : N-[2-(8-Hexyl-7-hydroxy-1-naphthyl)ethyll-2-phenylacetamide Preparation 5: N-Cyclopropylmethyl-2-(7-hydroxy-1-naphthyl)acetamide -31 Preparation 6: N-Cyclohexyl-4-(7-hydroxy--naphthyl)butanamide Preparation 7: N-[2-(7-Hydroxy-l-naphthyl)ethyl]-N-methyl-N'-propylurea Preparation 8 : N-[3-(7-Hydroxy-1-naphthyl)propylj acetamide Preparation 9 : N-[2-(7-Hydroxy-1-naphthyl)ethylJ-3-butenamide 5 Preparation 10 : N-[3-(7-Hydroxy-1-naphthyl)propylj -1-cyclohexanecarboxamide Preparation 11 : N-[2-(2-Hydroxy-l-naphthyl)ethylJ-2,2,2-trifluoroacetamide Preparation 12: N-[2-(2-Hydroxy-l-naphthyl)-l-methylethyljpropanamide Preparation 13 : N-[2-(7-Hydroxy-3-phenyl-1-naphthyl)ethyl] acetamide Preparation 14 : N-[2-(3-Benzoyl-7-hydroxy--naphthyl)ethyl]-N'-propylurea 10 Preparation 15 : N- 12- [3-(Cyclopropylmethyl)-7-hydroxy-1-naphthyl] ethyl) acetamide Preparation 16 : N-[3-(5-Hydroxybenzo [b] furan-3-yl)propyli acetamide Preparation 17 : N-Methyl-4-(5-hydroxybenzo [hifuran-3-yl)butanamide Preparation 18 : N-[2-(5-Hydroxybenzo Iblfuran-3-yl)ethylI acetamide Preparation 19 : N-[(2-Benzyl-5-hydroxybenzo [bJ thiophen-3-yl)methyl] acetamide 15 Preparation 20 : N-[2-(5-Hydroxythieno 13,2-bl pyridin-3-yl)ethyl] acetamide ____Preparation 21 : N-12-(5-Hydroxy-JH-3-indolyl)ethyll beozamide -32 Preparation 22 : N-{2-[2-(4-Fluorobenzyl)-5-hydroxy-1-methyl-1H-pyrrolo[2,3-bipyridin 3-yl] ethyl} acetamide Preparation 23 : N-[2-(2-Benzyl-5-hydroxybenzo[b]furan-3-yl)ethyl]-1-cyclopropane carboxamide 5 Preparation 24 : N-[(6-Hydroxy-3,4-dihydro-2H-3-chromenyl)methyl]acetamide Preparation 25 : N-[2-(6-Hydroxy-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide Preparation 26: N-[(6-Hydroxy-2-phenyl-2H-3-chromenyl)methyl]acetamide Preparation 27: N-[(6-Hydroxy-2-phenyl-2H-3-chromenyl)methyl]butanamide Preparation 28 : N-[2-(6-Hydroxy-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamide 10 Preparation 29 : N-[2-(7-Hydroxy-1,4-benzodioxin-2-yl)ethyl-N'-propylurea Preparation 30 : N-[2-(7-Hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl)ethyl]acetamide Preparation 31: N-[2-(6-Hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide Preparation 32: N-[(9-Hydroxy-2,3-dihydro-1H-benzo[/]chromen-2-yl)methyl]-2 cyclopropylacetamide 15 Preparation 33 : N-Cyclopropyl-N'-(4-hydroxy-2,3-dihydro-JH-2-phenalenyl)thiourea Preparation 34: N-Cyclobutyl-3-hydroxy-4,5-dihydro-3H-benzo[cdisobenzofuran-4 carboxamide Preparation 35 : N- {2-[7-Hydroxy-3-naphthyl-1-naphthyljethyl}heptanamide -33 Preparation 36 : N-[2-(7-Hydroxy-1,2,3,4-tetrahydro-1-naphthyl)ethyllacetamide Preparation 37: N-[2-(6-Hydroxy-2,3-dihydro-H-1-indenyl)ethylacetamide Preparation 38 : N-Cyclohexyl-4-(7-chloro-1-naphthyl)butanamide Chlorine (10 mmol) is bubbled into dichlorophenylphosphine at a flow rate such that the reaction 5 temperature is maintained between 70 and 80*C. After all the chlorine has been added, the phenylphosphine tetrachloride so obtained is a pale yellow liquid. 10 mmol of the product obtained in Preparation 5 are added all at once and the reaction mixture is heated at 160'C overnight. After cooling, the solution is poured into a water/ice mixture (20 ml) and is neutralised with a 50 % aqueous solution of sodium hydroxide. After extraction with ether, the 10 organic phases are dried and concentrated under reduced pressure to yield a residue, which is chromatographed on silica gel to obtain the pure title product. In Preparation 39, the procedure is as in Preparation 38, but the appropriate starting compound is used. Preparation 39: N-[(6-Chloro-3,4-dihydro-2H-3-chromenyl)methylacetamide 115 Starting compound: Preparation 24 Preparation 40 : N-[2-(7-Bromo-1-naphthyl)ethyl]-2-phenylacetamide Triphenylphosphine (10 mmol) and acetonitrile (70 ml) are poured into a 150 ml three-necked flask equipped with a bromine funnel, a condenser surmounted by a tube filled with calcium chloride and a mechanical stirrer. The solution is cooled with the aid of an ice bath, with stirring, 20 and bromine is added (10 mmol). At the end of the addition, the ice bath is removed and the product obtained in Preparation 2 (8 mmol) is then added. The reaction mixture is stirred at 60-70*C until the starting compound has disappeared (monitored by TLC). At the end of the reaction, the mixture is filtered and the filtrate is then concentrated under reduced pressure. The esidue is taken up in ethyl acetate, washed with water and then with saturated potassium -34 hydrogen carbonate solution and once again with water, and is then dried over magnesium sulphate and concentrated under reduced pressure. The residue is filtered through silica gel to yield the title product. In Preparations 41 to 72.1, the procedure is as in Preparation 40, starting from the appropriate 5 reactant. Preparation 41 : N-Cyclopropylmethyl-2-(7-bromo-1-naphthyl)acetamide Starting compound: Preparation 5 Preparation 42: N-[2-(7-Bromo-1-naphthyl)ethyll-N-methyl-N'-propylurea Starting compound: Preparation 7 10 Preparation 43 : N-[3-(7-Bromo-1-naphthyl)propyll-1-cyclohexanecarboxamide Starting compound: Preparation 10 Preparation 44 : N-[2-(2-Bromo-1-naphthyl)ethyl]-2,2,2-trifluoroacetamide Starting compound: Preparation 11 Preparation 45: N-[2-(3-Benzoyl-7-bromo-1-naphthyl)ethyll-N'-propylurea 15 Starting compound: Preparation 14 Preparation 46: N-[3-(5-Bromobenzo[b]furan-3-yl)propyl]acetamide Starting compound : Preparation 16 Preparation 47: N-[(2-Benzyl-5-bromobenzo[b]thiophen-3-yl)methyl]acetamide Starting compound: Preparation 19 20 Preparation 48: N-[2-(5-Bromo-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3 yl)ethylacetamide Starting compound: Preparation 22 -35 Preparation 49: N-[2-(6-Bromo-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide Starting compound: Preparation 25 Preparation 50: N-[(6-Bromo-2-phenyl-2H-3-chromenyl)methyl]acetamide Starting compound: Preparation 26 5 Preparation 51 : N-[2-(6-Bromo-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamide Starting compound: Preparation 28 Preparation 52 : N-[2-(7-Bromo-1,4-benzodioxin-2-yl)ethyll-N'-propylurea Starting compound : Preparation 29 Preparation 53 : N-[2-(6-Bromo-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide 10 Starting compound: Preparation 31 Preparation 54: N-[(9-Bromo-2,3-dihydro-1H-benzo[]chromen-2-yl)methyl]-2 cyclopropylacetamide Starting compound: Preparation 32 Preparation 55 : N-(4-Bromo-2,3-dihydro-1H-2-phenalenyl)-N'-cyclopropylthiourea V5 Starting compound: Preparation 33 Preparation 56: N-Cyclobutyl-6-bromo-4,5-dihydro-3H-benzo[cdjisobenzofuran-4 carboxamide Starting compound: Preparation 34 Preparation 57: N-[2-(7-Bromo-3-naphthyl-1-naphthyl)ethyl]heptanamide 20 Starting compound: Preparation 35 Preparation 58: N-[2-(7-Bromo-1-naphthyl)ethyl]acetamide Starting compound: Preparation 1 -36 Preparation 59 : N-[2-(7-Bromo-1-naphthyl)ethyl]-3-butenamide Starting compound: Preparation 9 Preparation 60: N-[2-(7-Bromo-1-naphthyl)ethyl]-2-bromoacetamide Starting compound: Preparation 3 5 Preparation 61 : N-[2-(7-Bromo-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide Starting compound : Preparation 4 Preparation 62 : N-[3-(7-Bromo-1-naphthyl)propylacetamide Starting compound: Preparation 8 Preparation 63 : N-[2-(2-Bromo-1-naphthyl)-1-methylethyl]propanamide 10 Starting compound: Preparation 12 Preparation 64: N- {2- [7-Bromo-3-(cyclopropylmethyl)-1-naphthyl] ethyl}acetamide Starting compound: Preparation 15 Preparation 65 : N-Methyl-3-(5-bromobenzo[bjfuran-3-yl)butanamide Starting compound: Preparation 17 15 Preparation 66: N-[2-(5-Bromothieno[3,2-b]pyridin-3-yl)ethyllacetamide Starting compound: Preparation 20 Preparation 67: N-[2-(5-Bromo-JH-3-indolyl)ethyl]benzamide Starting compound: Preparation 21 Preparation 68 : N-[2-(2-Benzyl-5-bromobenzo[b]furan-3-yl)ethyl]-1-cyclopropane 20 carboxamide Starting compound: Preparation 23 -37 Preparation 69: N-[(6-Bromo-2-phenyl-2H-3-chromenyl)methylbutanamide Starting compound: Preparation 27 Preparation 70: N-[2-(6-Bromo-2,3-dihydro-1H-1-indenyl)ethyllacetamide Starting compound: Preparation 37 5 Preparation 71: N-[2-(7-Bromo-3-phenyl-1-naphthyl)ethylacetamide Starting compound: Preparation 13 Preparation 72 : N-[2-(5-Bromobenzo[bifuran-3-yl)ethyllacetamide Starting compound: Preparation 18 Preparation 72.1 : N-[2-7-Bromo-1,2,3,4-tetrahydro-1-naphthyl)ethylacetamide 10 Starting compound : Preparation 36 Preparation 73 : N-[2-(7-Iodo-1-naphthyl)ethyl]-2-phenylacetamide A mixture of the product obtained in Preparation 40 (2 mmol), potassium iodide (30 mmol) and copper(I) iodide (10 mmol) in hexamethylphosphoramide (6 ml) is heated at 150-160 0 C, with stirring, under a nitrogen atmosphere until 90 % conversion has been achieved (monitored by 115 TLC). Then, dilute hydrochloric acid, and then ether, are added and the mixture is then filtered to remove the insoluble copper(I) salts. The organic phase is separated off, washed with sodium sulphite solution and with water, dried over magnesium sulphate and evaporated to yield a residue which is chromatographed on silica gel to yield the title product. In Preparations 74 to 108 the procedure is as in Preparation 73, but the product of Preparation 40 20 is replaced by the appropriate substrate. Preparation 74 : N-Cyclopropylmethyl-2-(7-iodo-1-naphthyl)acetamide Starting compound: Preparation 41 -38 Preparation 75 : N-[2-(7-Iodo-1-naphthyl)ethyl]-N-methyl-N'-propylurea Starting compound: Preparation 42 Preparation 76: N-[3-(7-Iodo-1-naphthyl)propyl]-1-cyclohexanecarboxamide 5 Starting compound: Preparation 43 Preparation 77: N-[2-(2-Iodo-1-naphthyl)ethyl]-2,2,2-trifluoroacetamide Starting compound: Preparation 44 Preparation 78: N-[2-(3-Benzoyl-7-iodo--naphthyl)ethyl]-N'-propylurea Starting compound: Preparation 45 10 Preparation 79 : N-[3-(5-Iodobenzo[b]furan-3-yl)propyllacetamide Starting compound: Preparation 46 Preparation 80: N-[(2-Benzyl-5-iodobenzo[b]thiophen-3-yl)methyllacetamide Starting compound: Preparation 47 Preparation 81 : N-[2-(5-Iodo-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl) 15 ethyl]acetamide Starting compound: Preparation 48 Preparation 82: N-[(6-Iodo-3,4-dihydro-2H-3-chromenyl)methyl]acetamide Starting compound: Preparation 39 Preparation 83: N-[2-(6-Iodo-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide 20 Starting compound: Preparation 49 Preparation 84: N-[(6-Iodo-2-phenyl-2H-3-chromenyl)methylacetamide Starting compound: Preparation 50 -39 Preparation 85: N-[2-(6-Iodo-3,4-dihydro-2H-4-thiochromenyl)ethylacetamide Starting compound: Preparation 51 Preparation 86 : N-[2-(7-Iodo-1,4-benzodioxin-2-yl)ethyl]-N'-propylurea Starting compound: Preparation 52 5 Preparation 87: N-[2-(6-Iodo-2,3-dihydro-1,4-benzodioxin-5-yl)ethylacetamide Starting compound : Preparation 53 Preparation 88 : N-[(9-Iodo-2,3-dihydro-1H-benzo[f chromen-2-yl)methyl]-2-cyclopropyl acetamide Starting compound: Preparation 54 10 Preparation 89: N-(4-Iodo-2,3-dihydro-1H-2-phenalenyl)-N'-cyclopropylthiourea Starting compound: Preparation 55 Preparation 90: N-Cyclobutyl-6-iodo-4,5-dihydro-3H-benzo[cdJisobenzofuran-4 carboxamide Starting compound: Preparation 56 115 Preparation 91 : N-[2-(7-Iodo-3-naphthyl-1-naphthyl)ethylheptanamide Starting compound: Preparation 57 Preparation 92 : N-[2-(7-Iodo-1-naphthyl)ethyllacetamide Starting compound: Preparation 58 Preparation 93 : N-[2-(7-Iodo-1-naphthyl)ethyl]-3-butenamide 20 Starting compound: Preparation 59 Preparation 94 : N-[2-(7-Iodo-1-naphthyl)ethyl]-2-bromoacetamide Starting compound: Preparation 60 T 7 -40 Preparation 95 : N-[2-(7-Iodo-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide Starting compound: Preparation 61 Preparation 96 : N-Cyclohexyl-4-(7-iodo-1-naphthyl)butanamide Starting compound: Preparation 38 5 Preparation 97: N-[3-(7-Iodo-1-naphthyl)propyl]acetamide Starting compound: Preparation 62 Preparation 98: N-[2-(2-Iodo-1-naphthyl)-1-methylethyllpropanamide Starting compound : Preparation 63 Preparation 99 : N-{2-[7-Iodo-3-(cyclopropylmethyl)-1-naphthyl ethyl}acetamide 10 Starting compound: Preparation 64 Preparation 100 : N-Methyl-4-(5-iodobenzo[bifuran-3-yl)butanamide Starting compound : Preparation 65 Preparation 101 : N-[2-(5-Iodothieno[3,2-b]pyridin-3-yl)ethyl]acetamide Starting compound: Preparation 66 15 Preparation 102 : N-[2-(5-Iodo-1H-3-indolyl)ethyllbenzamide Starting compound: Preparation 67 Preparation 103 : N-[2-(2-Benzyl-5-iodobenzo[b]furan-3-yl)ethyl]-1-cyclopropane carboxamide Starting compound: Preparation 68 20 Preparation 104 : N-[(6-Iodo-2-phenyl-2H-3-chromenyl)methyl]butanamide Starting compound: Preparation 69 -41 Preparation 105 : N-[2-(6-Iodo-2,3-dihydro-1H-1-indenyl)ethylacetamide Starting compound: Preparation 70 Preparation 106 : N-[2-(7-Iodo-3-phenyl-1-naphthyl)ethylacetamide Starting compound: Preparation 71 5 Preparation 107: N-[2-(7-Iodo-1,2,3,4-tetrahydro-1-naphthyl)ethylacetamide Starting compound: Preparation 72.1 Preparation 108 : N-[2-(5-Iodobenzo[b]furan-3-yl)ethyllacetamide Starting compound: Preparation 72 Preparation 109 : N-[2-(7-Amino-1-naphthyl)ethyl]-2-phenylacetamide 10 Step A : N-[2-(7-Vinyl-1-naphthyl)ethyl]-2-phenylacetamide 15 mmol of the product obtained in Preparation 73, 16 mmol of vinyltributyltin and 0.43 mmol of tetrakis(triphenylphosphine)palladium are heated in 30 ml of N-methylpyrrolidinone at 1 10*C for 3 hours, with stirring. After evaporating off the solvent, the residue is taken up in 20 ml of dichloromethane and treated with 10 % aqueous potassium fluoride solution. After extraction, 5 concentration under reduced pressure and chromatography on silica gel, the pure title product is obtained. Step B: N-[2-(7-Formyl-1-naphthyl)ethyl]-2-phenylacetamide To a solution of 10 mmol of the product obtained in Step A in a mixture of 50 ml of dioxane and 25 ml of water there are added, at ambient temperature, 1.10 g of osmium tetroxide in 2-methyl 20 2-propanol and then 8.70 g of sodium periodate. After stirring overnight at ambient temperature, the suspension is filtered and the filtrate is concentrated under reduced pressure. The residue obtained is taken up in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is purified by chromatography on silica gel to yield the title product.
- 42 Step C: 8-{2-[(2-Phenylacetyl)amino]ethyl}-2-naphthoic acid 2.7 g of potassium permanganate in 50 ml of an acetone/water mixture (50/50) are added, at ambient temperature, to a solution of 6.88 mmol of the product obtained in Step B in 30 ml of acetone. The solution is stirred for 2 hours at ambient temperature and is then filtered. The 5 filtrate is concentrated under reduced pressure and chromatographed on silica gel to yield the title product. Step D: 8-{2-[(2-Phenylacetyl)amino]ethyl}-2-naphthalenecarbonyl chloride 5 mmol of the product obtained in Step C are dissolved in 40 ml of thionyl chloride. After stirring under an inert atmosphere for 1 hour, the thionyl chloride is evaporated off under reduced 10 pressure to yield the title product. Step E: N-[2-(7-Amino-1-naphthyl)ethyl]-2-phenylacetamide A solution of the product obtained in Step D (20 mmol) in dichloromethane (30 ml) containing tetrabutylammonium bromide (20 mg) is cooled in an ice bath. After adding sodium azide (24 mmol) dissolved in 5 ml of water, the solution is stirred vigorously at 0*C for 2 hours. The 15 organic phase is separated off, washed with water (2 x 5 ml) and dried over magnesium sulphate. After filtration, trifluoroacetic acid (30 mmol) is added and the solution is stirred under reflux for 60 hours. After cooling, the organic phase is washed with saturated sodium hydrogen carbonate solution (2 x 5 ml) and is concentrated under reduced pressure. The residue is then taken up in methanol (20 ml); water (80 ml) and then potassium carbonate (30 mmol) are added. After 20 stirring at ambient temperature for 20 hours, the reaction mixture is concentrated under reduced pressure to a volume of about 60 ml and is then extracted 3 times with ether (3 x 50 ml). After drying over sodium sulphate, the organic phase is filtered and then evaporated under reduced pressure. The residue is chromatographed on silica gel to yield the title product. In Preparations 110 to 134 the procedure is as in Example 109, starting from the appropriate 25 substrate.
-43 Preparation 110 : N-[2-(7-Amino-1-naphthyl)ethyl]-2-bromoacetamide Starting compound: Preparation 94 Preparation 111 : N-[2-(7-Amino-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide Starting compound: Preparation 95 5 Preparation 112 : N-Cyclohexyl-4-(7-amino-1-naphthyl)butanamide Starting compound: Preparation 96 Preparation 113 : N-[3-(7-Amino-1-naphthyl)propyllacetamide Starting compound: Preparation 97 Preparation 114: N-[2-(2-Amino-1-naphthyl)-1-methylethyllpropanamide 10 Starting compound: Preparation 98 Preparation 115 : N-[2-(7-Amino-3-benzoyl-1-naphthyl)ethyl]-N'-propylurea Starting compound: Preparation 78 Preparation 116: N-[2-(7-Amino-1-naphthyl)ethyl]-3-butenamide Starting compound: Preparation 93 15 Preparation 117: N-[2-(7-Amino-1-naphthyl)ethyllacetamide Starting compound: Preparation 92 Preparation 118 : N- {2-[7-Amino-3-(cyclopropylmethyl)-1-naphthyll ethyl}acetamide Starting compound: Preparation 99 Preparation 119 : N-Methyl-4-(5-aminobenzo[bfuran-3-yl)butanamide 20 Starting compound: Preparation 100 Preparation 120 : N-[2-(5-Aminothieno[3,2-blpyridin-3-yl)ethyllacetamide Starting compound: Preparation 101 -44 Preparation 121 : N-[2-(5-Amino-JH-3-indolyl)ethyl]benzamide Starting compound: Preparation 102 Preparation 122 : N-{2-[5-Amino-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3 ylI ethyl) acetamide 5 Starting compound: Preparation 81 Preparation 123 : N-[2-(5-Amino-2-benzylbenzo[b]furan-3-yl)ethyl]-1-cyclopropane carboxamide Starting compound: Preparation 103 Preparation 124: N-[(6-Amino-3,4-dihydro-2H-3-chromenyl)methylacetamide 10 Starting compound : Preparation 82 Preparation 125 : N-[(6-Amino-2-phenyl-2H-3-chromenyl)methyl]butanamide Starting compound: Preparation 104 Preparation 126 : N-[2-(6-Amino-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide Starting compound: Preparation 87 15 Preparation 127 : N-[(9-Amino-2,3-dihydro-1H-benzo[fJchromen-2-yl)methyl]-2-cyclo propylacetamide Starting compound : Preparation 88 Preparation 128 : N-(4-Amino-2,3-dihydro-1H-2-phenalenyl)-N'-cyclopropylthiourea Starting compound: Preparation 89 20 Preparation 129 : N-[2-(7-Amino-3-phenyl-1-naphthyl)ethylacetamide Starting compound: Preparation 106 -7 -45 Preparation 130 : N-Cyclobutyl-6-amino-4,5-dihydro-3H-benzo[cd]isobenzofuran-4 carboxamide Starting compound: Preparation 90 Preparation 131 : N-[2-(7-Amino-3-naphthyl-1-naphthyl)ethyl]heptanamide 5 Starting compound: Preparation 91 Preparation 132 : N-[2-(5-Aminobenzojb]furan-3-yl)ethyljacetamide Starting compound: Preparation 108 Preparation 133 : N-[2-(7-Amino-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide Starting compound: Preparation 107 10 Preparation 134: N-[2-(6-Amino-2,3-dihydro-1H-1-indenyl)ethyllacetamide Starting compound: Preparation 105 Preparations 135 to 145 are obtained by proceeding as in Preparation 1, starting from the appropriate substrate. Preparation 135: N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-furamide 15 Preparation 136 : N-[2-(7-Hydroxy-1-naphthyl)ethylbenzamide Preparation 137: N-12-(7-Hydroxy-1-naphthyl)ethyllcyclopropanecarboxamide Preparation 138 : N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethylbenzamide Preparation 139 : N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]-2-furamide Preparation 140 : N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide GT re aration 141 : N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethyllcyclopropanecarboxamide -46 Preparation 142 : N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide Preparation 143 : N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyllcyclopropane carboxamide Preparation 144 : N-[2-(5-Hydroxy-1H-pyrrolo[2,3-bjpyridin-3-yl)ethyllbenzamide 5 Preparation 145 : N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide Preparation 146 : N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyllacetamide The procedure is as in Preparation 40, starting from the compound obtained in Preparation 142. Preparation 147: N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide The procedure is as in Preparation 73, starting from the compound obtained in Preparation 146. 10 Preparation 148: N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide The procedure is as in Preparation 109, starting from the compound obtained in Preparation 147. Preparation 149 : N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide The procedure is as in Preparation 40, starting from the compound obtained in Preparation 145. Preparation 150 : N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide 15 The procedure is as in Preparation 73, starting from the compound obtained in Preparation 149. 77 -47 Preparation 151 : N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide The procedure is as in Preparation 109, starting from the compound obtained in Preparation 150. Preparation 152 : N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide The procedure is as in Preparation 40, starting from the compound obtained in Preparation 144. 5 Preparation 153 : N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide The procedure is as in Preparation 73, starting from the compound obtained in Preparation 152. Preparation 154 : N-[2-(5-Amino-1H-pyrrolo[2,3-blpyridin-3-yl)ethyl]benzamide The procedure is as in Preparation 109, starting from the compound obtained in Preparation 153. Preparation 155 : N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane 10 carboxamide The procedure is as in Preparation 40, starting from the compound obtained in Preparation 143. Preparation 156 : N-[2-(5-Iodo-1H-pyrrolo[2,3-blpyridin-3-yl)ethyl]cyclopropane carboxamide The procedure is as in Preparation 73, starting from the compound obtained in Preparation 155. 15 Preparation 157 : N-[2-(5-Amino-JH-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane carboxamide The procedure is as in Preparation 109, starting from the compound obtained in Preparation 156. ~T II- -48 Preparation 158 : N-[2-(5-Hydroxy-1H-pyrrolo[3,2-bjpyridin-3-yl)ethyl]cyclopropane carboxamide The procedure is as in Preparation 1. Preparation 159: N-[2-(5-Bromo-1H-pyrrolo[3,2-blpyridin-3-yl)ethyl]cyclopropane 5 carboxamide The procedure is as in Preparation 40, starting from the compound obtained in Preparation 158. Preparation 160 : N-[2-(5-Iodo-1H-pyrrolo[3,2-bjpyridin-3-yl)ethyl]cyclopropane carboxamide The procedure is as in Preparation 73, starting from the compound obtained in Preparation 159. 10 Preparation 161 : N-[2-(5-Amino-1H-pyrrolo[3,2-blpyridin-3-yl)ethyl]cyclopropane carboxamide The procedure is as in Preparation 109, starting from the compound obtained in Preparation 160. Preparation 162 : N-[2-(5-Hydroxy-1H-pyrrolo[3,2-blpyridin-3-yl)ethyl]acetamide The procedure is as in Preparation 1. 15 Preparation 163 : N-[2-(5-Bromo-1H-pyrrolo[3,2-bjpyridin-3-yl)ethyl]acetamide The procedure is as in Preparation 40, starting from the compound obtained in Preparation 162. Preparation 164: N-[2-(5-Iodo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide The procedure is as in Preparation 73, starting from the compound obtained in Preparation 163.
- 49 Preparation 165 : N-[2-(5-Amino-1H-pyrrolo[3,2-blpyridin-3-yl)ethyl]acetamide The procedure is as in Preparation 109, starting from the compound obtained in Preparation 164. Preparation 166 : N-[2-(5-Bromo-1-benzofuran-3-yl)ethylcyclopropanecarboxamide The procedure is as in Preparation 40, starting from the compound obtained in Preparation 140. 5 Preparation 167: N-[2-(5-Iodo-1-benzofuran-3-yl)ethylcyclopropanecarboxamide The procedure is as in Preparation 73, starting from the compound obtained in Preparation 166. Preparation 168 : N-[2-(5-Amino-1-benzofuran-3-yl)ethyllcyclopropanecarboxamide The procedure is as in Preparation 109, starting from the compound obtained in Preparation 167. Preparation 169 : N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethylbenzamide 10 The procedure is as in Preparation 1. Preparation 170 : N-[2-(5-Bromo-1-benzothiophen-3-yl)ethylbenzamide The procedure is as in Preparation 40, starting from the compound obtained in Preparation 169. Preparation 171 : N-[2-(5-Iodo-1-benzothiophen-3-yl)ethylbenzamide The procedure is as in Preparation 73, starting from the compound obtained in Preparation 170. 15 Preparation 172 : N-[2-(5-Amino-1-benzothiophen-3-yl)ethyllbenzamide The procedure is as in Preparation 109, starting from the compound obtained in Preparation 171. IYz -50 Preparation 173 : N-[2-(7-Bromo-1-naphthyl)ethyl]-2-furamide The procedure is as in Preparation 40, starting from the compound obtained in Preparation 135. Preparation 174 : N-[2-(7-Iodo-1-naphthyl)ethyl]-2-furamide The procedure is as in Preparation 73, starting from the compound obtained in Preparation 173. 5 Preparation 175 : N-[2-(5-Bromo-1-benzofuran-3-yl)ethyl]benzamide The procedure is as in Preparation 40, starting from the compound obtained in Preparation 138. Preparation 176: N-[2-(5-Iodo-1-benzofuran-3-yl)ethyllbenzamide The procedure is as in Preparation 73, starting from the compound obtained in Preparation 176. EXAMPLE 1: N-{8-[2-([2-Phenylacetyl]amino)ethyl]-2-naphthyl}butanamide 10 A solution of butanoic acid chloride (11 mmol) dissolved in ether (5 ml) is added dropwise to a solution of the product obtained in Preparation 109 (10 mmol) in ether (10 ml) and triethylamine (2 ml). The solution is stirred at ambient temperature until the amine has disappeared (monitored by TLC). At the end of the reaction, the organic phase is washed with water, dried, concentrated 15 under reduced pressure and chromatographed on silica gel to yield the title product. EXAMPLE 2: N-{2-[7-{[(Cyclohexylamino)carbonylamino)-1-naphthyllethyl}-2 phenylacetamide A solution of cyclohexyl isocyanate in dichloromethane (5 ml) is added to a solution of the 20 product obtained in Preparation 109 (10 mmol) in dichloromethane (10 ml). Stirring is carried out at ambient temperature until the starting amine has disappeared (monitored by TLC); the reaction mixture is then evaporated and concentrated under reduced pressure and is hromatographed on silica gel to yield the title product.
-51 EXAMPLE 3: N-{2-[7-([Anilinocarbothioyl]amino)-1-naphthyllethyl)-2-phenyl acetamide The procedure is as in Example 2, but the cyclohexyl isocyanate is replaced by phenyl 5 isothiocyanate to obtain the title product. In Examples 4 to 16 the procedure is as in Example 1, starting from appropriate reactants. EXAMPLE 4: N-(8-{2-[(2-Bromoacetyl)amino]ethyl}-2-naphthyl)-1-cyclohexane carboxamide Starting compound: Preparation 110 10 EXAMPLE 5: N-{1-Hexyl-8-[2-([2-phenylacetyllamino)ethyl]-2-naphthyl}benzamide Starting compound: Preparation 111 EXAMPLE 6: N-{6-Benzoyl-8-[2-{[(propylamino)carbonyllamino)ethyl]-2-naphthyl} 15 2,2-dimethylpropanamide Starting compound: Preparation 115 EXAMPLE 7: N-3-[4-(Mthylamino)-4-oxobutyllbenzo[blfuran-5-yl}-3-butynamide Starting compound: Preparation 119 20 EXAMPLE 8: N-{3-[2-(Acetylamino)ethyl]-2-[4-fluorobenzyl]-1-methyl-1H-pyrrolo [2,3-b]pyridin-5-yl}-3-phenyl-2-propenamide Starting compound: Preparation 122 25 EXAMPLE 9: N-{3-[(Acetylamino)methyl]-3,4-dihydro-2H-6-chromenyl}-2-phenyl propanamide Starting compound: Preparation 124 e4--- v-, - 52 EXAMPLE 10: N-{5-[2-(Acetylamino)ethyl]-2,3-dihydro-1,4-benzodioxin-6-yl} hexanamide Starting compound: Preparation 126 5 EXAMPLE 11 : N-{2-[([2-Cyclopropylacetyl]amino)methyl]-2,3-dihydro-1H-benzo[/] chromen-9-yl}-4-(trifluoromethyl)benzamide Starting compound: Preparation 127 EXAMPLE 12: N-{2-[([Cyclopropylamino]carbothioyl)amino]-2,3-dihydro-1H-4 10 phenalenyl}-4-ethoxybenzamide Starting compound: Preparation 128 EXAMPLE 13: N-{8-[2-(Acetylamino)ethyl]-6-phenyl-2-naphthyl}-1-cyclopentane carboxamide 15 Starting compound: Preparation 129 EXAMPLE 14: N-Cyclobutyl-6-([2-cyclopropylacetyl)amino]-4,5-dihydro-3H-benzo[cdl isobenzofuran-4-carboxamide Starting compound: Preparation 130 EXAMPLE 15: N-{8-[2-(Heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide 20 Starting compound: Preparation 131 EXAMPLE 16: N- {2-[6-(Acetylamino)-2,3-dihydro-1H-1-indenyl] ethyl} acetamide Starting compound: Preparation 134 Examples 17 to 23 are obtained by proceeding as in Example 2, starting from appropriate reactants. 25 EXAMPLE 17: N-Cyclohexyl-4-{7-[(anilinocarbonyl)amino]-1-naphthyl}butanamide Starting compound: Preparation 112 - 53 EXAMPLE 18: N-{1-Methyl-2-[2-{[([morpholinomethyllamino)carbonyl]amino)-1 naphthyl] ethyl}propanamide Starting compound: Preparation 114 EXAMPLE 19: N-{2-[7- {[(Benzylamino)carbonyl] amino)-3-(cyclopropylmethyl)-1 5 naphthyl] ethyl) acetamide Starting compound: Preparation 118 EXAMPLE 20: N- {2-[5-{[(Allylamino)carbonyl] amino}thieno [3,2-b] pyridin-3-yl] ethyl) acetamide Starting compound: Preparation 120 10 EXAMPLE 21: N-{2-[2-Benzyl-5-{[(1-ethynylamino)carbonyl]amino}benzo[b]furan 3-ylethyl}-1-cyclopropanecarboxamide Starting compound: Preparation 123 EXAMPLE 22: N-{[6-{[([3-Methyl-2-butenyl]amino)carbonyljamino}-2-phenyl-2H-3 chromenyl]methyl}butanamide 15 Starting compound: Preparation 125 EXAMPLE 23: N-[2-(7-{[(Cyclohexylamino)carbonyl]amino}-3-phenyl-1-naphthyl) ethyl]acetamide Starting compound: Preparation 129 In Examples 24 to 29 the procedure is as in Example 3, starting from appropriate substrates. 20 EXAMPLE 24: N-{2-[7-{[(Isobutylamino)carbothioyllamino)-1-naphthyl]ethyl}-2 bromoacetamide Starting compound: Preparation 110 ST 7 z - 54 EXAMPLE 25: N-{3-[7-{[([4-Methylbenzyl]amino)carbothioyllamino}-1-naphthyl] propyl}acetamide Starting compound : Preparation 113 EXAMPLE 26: N-Methyl-4-{5-[([1-ethynylamino]carbothioyl)amino]benzo[b]furan-3 5 yI}butanamide Starting compound: Preparation 119 EXAMPLE 27: N-{2-[5-{ [(Butylamino)carbothioyll amino}-1H-3-indoly] ethyl} benzamide Starting compound: Preparation 121 0 EXAMPLE 28 : N-{19-([Anilinocarbothioyl]amino)-2,3-dihydro-1H-benzo[]chromen-2 ylImethyl}-2-cyclopropylacetamide Starting compound: Preparation 127 EXAMPLE 29: N-Cyclobutyl-6-{[([2,3-dimethyl-2-butenyl]amino)carbothioyl]amino}-4,5 dihydro-3H-benzo[cdlisobenzofuran-4-carboxamide 5 Starting compound: Preparation 130 EXAMPLE 30: N-Ethyl-8-{2-[(2-phenylacetyl)aminolethyl}-2-naphthamide The procedure is as in Preparation 109, but instead of converting the acid chloride into an amine, it is treated with an amine to yield the title amide according to the procedure described below. A solution of the product obtained in Step D of Preparation 109 (3.5 mmol) in ether (10 ml) is o added, dropwise, to a solution of ethylamine (4 mmol) in ether (10 ml) and triethylamine (2 ml), maintained between 0 and 5*C using an ice bath. Stirring is carried out at ambient temperature until the acid chloride has disappeared and the reaction mixture is then poured into a mixture of ice (10 g) and concentrated HCl (0.1 ml). The organic phase is washed with water, dried over magnesium sulphate, concentrated under reduced pressure and chromatographed on silica gel to sTF-4 d the title product.
-55 In Examples 31 to 50 the procedure is as in Example 30, but the ethylamine and the product of Step D of Preparation 109 are replaced by appropriate substrates. EXAMPLE 31 : N,N-Diethyl-8-{2-[2-[(cyclopropylmethyl)amino]-2-oxoethyl}-2 naphthamide 5 Starting compound: Preparation 74 EXAMPLE 32: N-Phenyl-8-(2-{methyl[(propylamino)carbonylamino}ethyl)-2 naphthamide Starting compound: Preparation 75 EXAMPLE 33: N-(1-Ethynyl)-8-{2-[(cyclohexylcarbonyl)amino]ethyl}-2-naphthamide 10 Starting compound: Preparation 76 EXAMPLE 34: N-Benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide Starting compound: Preparation 77 EXAMPLE 35: N-{2-[3-Benzoyl-7-(morpholinocarbonyl)-1-naphthyllethyl}-N' propylurea 15 Starting compound: Preparation 78 EXAMPLE 36: N,N-Diphenyl-3-[3-(acetylamino)propyljbenzo[b]furan-5-carboxamide Starting compound : Preparation 79 EXAMPLE 37: N-Isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b] thiophene-5-carboxamide 20 Starting compound: Preparation 80 EXAMPLE 38: N,N-Diethyl-3-[2-(acetylamino)ethyl]-2-(4-fluorobenzyl)-1-methyl-1H pyrrolo[2,3-b]pyridine-5-carboxamide Starting compound: Preparation 81
T-
- 56 EXAMPLE 39: Ethyl 2-{[(4-{2-[(2-phenylacetyl)aminolethyl}-3,4-dihydro-2H-6 chromenyl)carbonyl] amino}acetate Starting compound: Preparation 83 EXAMPLE 40: N-Cyclohexyl-N-(1-ethynyl)-4-[2-(acetylamino)ethyl]-6-thiochroman carboxamide Starting compound: Preparation 85 5 EXAMPLE 41 : N-Benzyl-3-(2-{[(propylamino)carbonylamino}ethyl-1,4-benzodioxin-6 carboxamide Starting compound: Preparation 86 EXAMPLE 42: N-(3-Methyl-2-butenyl)-2-{[(2-cyclopropylacetyl)aminolmethyl) 2,3,6,10b-tetrahydro-1H-benzo[f]chromene-8-carboxamide Starting compound: Preparation 88 10 EXAMPLE 43: N-[3-Phenyl-2-propenyl]-2-{[(cyclopropylamino)carbothioyllamino}-2,3 dihydro-JH-4-phenalenecarboxamide Starting compound: Preparation 89 EXAMPLE 44: N-Cyclobutyl-N-trityl-4,5-dihydro-3H-benzo[cdJisobenzofuran-4,6 dicarboxamide 15 Starting compound: Preparation 90 EXAMPLE 45: Ethyl 2-[({8-[2-heptanoylamino)ethyl]-6-naphthyl-2-naphthyl)carbonyl) amino]acetate Starting compound: Preparation 91 EXAMPLE 46: N-(1-Ethynyl)-8-{2-[(2-bromoacetyl)amino]ethyl)-2-naphthamide 20 Starting compound: Preparation 94 7)ST -57 EXAMPLE 47: N-Phenyl-1-hexyl-8-{2-[(2-phenylacetyl)aminolethyl)-2-naphthamide Starting compound : Preparation 95 EXAMPLE 48: Ethyl 2-({{8-[2-(acetylamino)ethyl]-6-(cyclopropylmethyl)-2-naphthyl] carbonyl}amino)acetate 5 Starting compound: Preparation 99 EXAMPLE 49: N-(1-Ethynyl)-2-benzyl-3-{2-[(cyclopropylcarbonyl)amino] ethyl) benzo [b]furan-5-carboxamide Starting compound : Preparation 103 EXAMPLE 50: N-(1-Isopropyl-2-propynyl)-3-[(butynylamino)methyl]-2-phenyl-2H-6 chromenecarboxamide 10 Starting compound: Preparation 104 EXAMPLE 51 : N-Phenyl-8-(2- {methyll(propylamino)carbothioyl] amino) ethyl)-2 naphthalenecarbothioamide The product obtained in Example 32 is treated with Lawesson's reagent to yield the title compound. 15 In Examples 52 to 57 the procedure is as in Example 51, taking the appropriate starting substrate. EXAMPLE 52: N-Benzyl-1- (2-[(2,2,2-trifluoroethanethioyl)aminoI ethyl}-2-naphthalene carbothioamide Starting compound: Example 34 EXAMPLE 53: N,N-Diphenyl-3-[3-(ethanethioylamino)propylbenzo[b]furan-5 20 carbothioamide Starting compound: Example 36 - 58 EXAMPLE 54: N,N-Diethyl-3-[2-(ethanethioylamino)ethyl]-2-(4-fluorobenzyl)-1-methyl 1H-pyrrolo[2,3-b]pyridine-5-carbothioamide Starting compound: Example 38 EXAMPLE 55: N-Cyclohexyl-N-(1-ethynyl)-4-[2-(ethanethioylamino)ethyl]-6 5 thiochromancarbothioamide Starting compound: Example 40 EXAMPLE 56: N-(3-Methyl-2-butenyl)-2-{[(2-cyclopropylethanethioyl)amino]methyl} 2,3,6,10b-tetrahydro-JH-benzo[f]chromene-8-carbothioamide Starting compound: Example 42 10 EXAMPLE 57: N-[3-Phenyl-2-propenyl]-2-{[(cyclopropylamino)carbothioyllamino}-2,3 dihydro-1H-4-phenalenecarbothioamide Starting compound: Example 43 In Examples 58 to 61 the procedure is as in Example 1, but the acid chloride is replaced by the corresponding halogenocarboxylate. 15 EXAMPLE 58: Methyl N-{3-[2-(acetylamino)ethyl]benzo[blfuran-5-yl)carbamate Starting compound: Preparation 132 Melting point = 138-140'C EXAMPLE 59: Ethyl N-(8-{2-[(2-bromoacetyl)aminojethyl}-2-naphthyl)carbamate Starting compound: Preparation 110 20 EXAMPLE 60: Methyl N-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate Starting compound: Preparation 129 EXAMPLE 61 : Hexyl N-{8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl} carbamate Starting compound: Preparation 133
T
- 59 EXAMPLE 62: N-[2-(5-Methoxycarbonylbenzo[blfuran-3-yl)ethyl]acetamide Step A : 3-Acetyl-4-hydroxybenzoic acid 166 mmol of aluminium chloride are added slowly to 150 ml of nitrobenzene. 83 mmol of 4 acetylbenzoic acid are then added and heating is carried out at 120*C for 2 hours. The mixture is 5 hydrolysed using 1.2 litres of ice-cold water and the aqueous phase is acidified with 20 ml of concentrated HCl. Then, extraction with ethyl acetate and washing with aqueous 5 % sodium carbonate solution are carried out. The aqueous phase is acidified with 6N HCl and the precipitate obtained is dried and recrystallised. Melting point = 120-121PC 10 Step B: 3-(2-Bromoacetyl)-4-hydroxybenzoic acid The compound obtained in Step A (32.2 mmol) is dissolved in glacial acetic acid (40 ml) and then 48.3 mmol of bromine are added. The mixture is heated at 80*C for 2 hours and is then hydrolysed using ice-cold water. The precipitate obtained is filtered off, washed with water until a pH of 5-6 is obtained, and then dried and recrystallised. 15 Melting point = 174-175'C Step C: Methyl 3-bromoacetyl-4-hydroxybenzoate The compound obtained in Step B (27.4 mmol) is dissolved in 150 ml of MeOH, and 54.8 mmol of thionyl chloride are added dropwise in the cold state. The mixture is then stirred for 1 hour at ambient temperature and then for 2 hours at reflux. After evaporating off the methanol and the 20 thionyl chloride, the oily residue is taken up in AcOEt, washed with water and then dried over MgSO 4 . The solvent is evaporated off under reduced pressure and the solid obtained is recrystallised. Melting point = 93-94'C 17Tf - 60 Step D: 5-(Methoxycarbonyl-3-benzo[b]furan-3-yl)acetonitrile The compound obtained in Step C (15 mmol) is dissolved in 35 ml of acetone. 30 mmol of potassium carbonate are added and the mixture is stirred for 2 hours at ambient temperature. The precipitate formed is filtered off, washed with acetone and the filtrate is evaporated under 5 reduced pressure. The benzofuranone formed is used directly in the following step : 22.5 mmol of NaH are introduced into a 250 ml round-bottomed two-necked flask which is placed in a bath of ice/salt and under a nitrogen atmosphere. 22.5 mmol of diethyl cyanophosphonate are added dropwise and the mixture is then stirred for 20 minutes. The benzofuranone previously obtained, in 140 ml of anhydrous THF, is added and the mixture is 10 stirred for 2 hours at ambient temperature. After hydrolysing on a pile of ice and extracting with Et 2 0, the organic phase is dried over MgSO 4 and the solvent is then evaporated off under reduced pressure. The title compound is purified by chromatography on a silica gel column (eluant:
CH
2 C1 2 ), and is then recrystallised. Melting point = 125-126 0 C 15 Step E: N-[2-(5-Methoxycarbonylbenzo[b]furan-3-yl)ethyl]acetamide The 5-(methoxycarbonylbenzo[b]furan-3-yl)acetonitrile obtained in Step D (6.46 mmol) is dissolved in acetic anhydride (30 ml) in an autoclave, and 14.4 mmol of Raney nickel are added. After stirring overnight at 60*C and under a hydrogen pressure of 60 bars, the catalyst is filtered off and washed with methanol. The filtrate is evaporated to dryness and the chestnut-coloured 20 precipitate obtained is chromatographed on a silica gel column using ethyl acetate as eluant and is then recrystallised. Melting point = 121-122'C Elemental microanalysis: C H N 25 % calculated: 64.36 5.78 5.36 %found: 64.14 5.81 5.28 -61 EXAMPLE 63: Methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate Step A : Methyl 3-(2-aminoethyl)-1-benzofuran-5-carboxylate hydrochloride 6.57 mmol of the compound obtained in Step D of Example 62 are dissolved in 150 ml of methanol. The solution is introduced into an autoclave and 28.8 mmol of Raney nickel are added. 5 The solution is saturated with ammonia, and then hydrogen is introduced until a pressure of 60 bars is obtained. The solution is stirred for 4 hours at a temperature of 60*C. After cooling, the catalyst is filtered off, and the methanol is then evaporated off. The residue is purified by chromatography on a silica gel column using a mixture of dichloromethane/methanol (7/3) and then methanol as eluant. The amine obtained is dissolved in absolute ethanol. Stirring is carried 10 out in an ice bath and gaseous hydrogen chloride is bubbled through. The hydrochloride obtained is filtered off under suction and dried in a desiccator. Melting point = 210-211'C Step B: Methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate 1 mmol of the compound obtained in Step A is introduced into 30 ml of anhydrous CH 2 Cl 2 . The 15 temperature is lowered with the aid of an ice bath, and 1.5 mmol of triethylamine and then 1.5 mmol of 2-furoic acid chloride are added dropwise in succession. The mixture is stirred for 20 minutes, and the organic phase is then washed with water, dried over MgSO 4 and evaporated. The residue is purified by chromatography on a silica gel column and the title product is recrystallised. 20 Melting point = 116-118'C Elemental microanalysis : C H N % calculated: 65.17 4.82 4.47 %found: 64.80 4.84 4.50
S
- 62 EXAMPLE 64: Methyl 3-{2-[(cyclopentylcarbonyl)amino] ethyl)-1-benzofuran-5 carboxylate The procedure is as in Example 63. Melting point = 122-123'C 5 EXAMPLE 65 : Methyl 3-{2-[(cyclopropylcarbonyl)aminolethyl}-1-benzofuran-5 carboxylate The procedure is as in Example 63. Melting point = 154-155'C EXAMPLE 66 : Methyl 3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate 10 Vinylacetic acid (1 mmol), 1-ethyl-3-(3-dimethylaminopropyl-3-ethyl)carbodiimide hydro chloride (E.D.C.) (1.1 mmol) and hydroxybenzotriazole (HOBT) (1.1 mmol) are dissolved in dichloromethane (30 ml) in a flask cooled to -20*C. After 30 minutes, the compound obtained in Step A of Example 63 (1 mmol), dissolved in dichloromethane (20 ml), is added dropwise. The reaction mixture is stirred for 30 minutes at -20*C and then overnight at ambient temperature. 15 The dichloromethane is evaporated off and the residue is purified by chromatography on a silica gel column. Melting point = 98-100'C EXAMPLE 67 : 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxamide The ester (0.1 mol) obtained in Example 62, dissolved in an aqueous 20% ammonium hydroxide 20 solution (50 ml), is heated for 5 hours at 60*C. The reaction mixture is cooled and is then evaporated to dryness. The residue obtained is purified by chromatography on a silica gel column. Melting point = 206-208'C - 63 Elemental microanalysis: C H N % calculated: 63.40 5.73 11.38 %found: 63.23 5.89 11.17 5 EXAMPLE 68: 3-{2-[(Cyclopropylcarbonyl)aminoj ethyl}-1-benzofuran-5-carboxamide The same procedure is used as in Example 67. Melting point = 209-210*C EXAMPLE 69: 3-[2-(2-Furoylamino)ethyl]-1-benzofuran-5-carboxamide The same procedure is used as in Example 67. [0 Melting point = 110-112 0 C Elemental microanalysis: C H N % calculated: 64.42 4.73 9.39 %found: 64.23 4.98 9.97 15 EXAMPLE 70: 3-{2-[(Cyclopropylcarbonyl)aminolethyl}-N-methyl-1-benzofuran-5 carboxamide To the ester obtained in Example 62 (1 mmol), dissolved in methanol (40 ml) in the hot state, there is added an aqueous 40 % methylamine solution (1.6 mmol), and the mixture is refluxed for 2 hours. The reaction mixture is then cooled and the methanol is subsequently evaporated off. 20 The aqueous phase is extracted with ethyl acetate, the organic phase is dried over magnesium sulphate and the solvent is evaporated off. The residue is purified by chromatography on a silica gel column. Melting point = 188-189'C S1 - 64 Elemental microanalysis: C H N % calculated: 67.11 6.34 9.78 %found: 67.00 6.34 9.77 5 EXAMPLE 71: 3-[2-(Acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide The same procedure is used as in Example 70. Melting point = 158-159*C Elemental microanalysis : C H N 10 % calculated: 64.59 6.20 10.76 %found: 64.27 6.13 10.44 EXAMPLE 72 : 3-{2-[(Cyclopentylcarbonyl)aminolethyl}-N-methyl-1-benzofuran-5 carboxamide The same procedure is used as in Example 70. 15 Melting point = 170-171*C EXAMPLE 73 : 3-[2-(Benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide The same procedure is used as in Example 70. EXAMPLE 74 : N-{3-[2-(Acetylamino)ethyll-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide Step A: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxylic acid 20 To the ester obtained in Example 62 (2 mmol), dissolved in methanol (90 ml), there is added aqueous 30 % sodium hydroxide solution (30 ml), and the mixture is stirred overnight. After evaporating off the methanol, the temperature of the reaction mixture is lowered with the aid of an ice bath and the mixture is acidified with hydrochloric acid solution (6N). The aqueous phase - 65 is extracted with ethyl acetate, and the organic phase is dried over magnesium sulphate and then evaporated to dryness. The residue obtained is recrystallised. Melting point = 210-211*C Step B.: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carbonyl azide 5 The acid (1 mmol) obtained in Step A is dissolved in acetone. The temperature of the reaction mixture is lowered with the aid of an ice bath, and triethylamine (1.5 mmol) and then ethyl chloroformate (1.5 mmol) are added. After stirring for 15 minutes, sodium azide (1.5 mmol), previously dissolved in water (1 ml of water per 400 mg of sodium azide), is added and stirring is again carried out for 10 minutes. The mixture is extracted with ethyl acetate, and the organic 10 phase is then washed with water, dried over magnesium sulphate and evaporated to dryness. The azide obtained is used, without additional purification, in the following Step. Step C: N-{3-[2-(Acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide To the azide obtained in Step B (460 mg, 1.68 mmol), dissolved in dichloromethane, there is added trifluoroacetic acid (1.82 ml, 2.35 mmol) and stirring is carried out overnight. The reaction 15 mixture is washed with water and then with aqueous 10 % sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate and then evaporated. The residue obtained is purified by chromatography on a silica gel column using ethyl acetate as eluant. Melting point = 152-154'C EXAMPLE 75: Methyl 3-{2-[(cyclopropylcarbonyl)aminojethyl}-1-benzofuran-5-yl 20 carbamate The azide obtained in Step B of Example 74 (1 mmol) is heated at 80*C overnight and 5 ml of MeOH and 5 ml of toluene are added. After evaporating off the solvent, the residue obtained is purified by chromatography on a silica gel column. Melting point = 153-155'C 7 - 66 Elemental microanalvsis: C H N % calculated: 63.56 6.00 9.27 %found: 63.27 6.02 9.14 5 EXAMPLE 76 : tert-Butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate The procedure is as in Examples 74 and 75. Melting point = 146-148'C Elemental microanalysis : C H N 10 % calculated: 64.12 6.97 8.79 %found: 64.03 6.58 8.67 EXAMPLE 77: tert-Butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate To 1.98 mmol of the carbamate obtained in Example 76, dissolved in dimethylformamide, there are added, in the cold state, 2.18 mmol of sodium hydride, and stirring is carried out for 2 hours 15 at ambient temperature. 2.37 mmol of methyl iodide are added to the mixture and stirring is carried out for 4 hours at ambient temperature. The reaction mixture is hydrolysed, extracted with ethyl acetate, and the organic phase is then washed with water and dried over magnesium sulphate. The residue is recrystallised. EXAMPLE 78 : Methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate 20 The procedure is as in Examples 74 and 75. EXAMPLE 79: Methyl 3-[2-(isobutyrylamino)ethyl]-1-benzofuran-5-yl-carbamate The procedure is as in Examples 74 and 75. ST 1 - 67 EXAMPLE 80: N-{2-[7-(Aminosulphonyl)-1-naphthyllethyl}acetamide Step A : N- {2-[7-(Benzylthio)- 1 -naphthyl] ethyl} acetamide 4.4 mmol of the compound obtained in Preparation 1 are dissolved in 20 ml of anhydrous CH 2 Cl 2 and placed under a current of nitrogen. 6.5 mmol of benzylthiol are added dropwise using a 5 syringe and then 8.8 mmol of triflic acid are added, before the mixture is refluxed for 24 hours. After cooling, hydrolysis is carried out using 10% Na 2
CO
3 solution. The organic phase is washed with 10 % sodium hydroxide solution and then with water until the washing waters are neutral, and is then dried and evaporated. The residue is taken up in petroleum ether and recrystallised from a toluene/cyclohexane mixture. 10 Melting point = 80-83'C Step B : 8-[2-(Acetylamino)ethyl]-2-naphthalenesulphonyl chloride 3 mmol of the compound obtained in Step A are crushed in a mortar, together with 13.1 mmol of iodosobenzene and 107 g of silica/HCl, with the aid of a pestle. Dichloromethane is added and the silica is filtered off and washed several times with CH 2 C1 2 . The filtrate obtained is evaporated 15 and the residue is taken up in petroleum ether and then filtered. Step C: N-{2-[7-(Aminosulphonyl)-1-naphthyl]ethyl}acetamide 0.8 mmol of the compound obtained in Step B is dissolved in 10 ml of CH 2 Cl 2 and then 1.2 mmol of triethylamine are added. The mixture is cooled with the aid of an ice bath and 1.2 mmol of ammonium hydroxide solution are added dropwise. After stirring for 2 hours, the 20 mixture is evaporated and the residue obtained is recrystallised. Melting point = 194-196 0 C EXAMPLE 81 : N-(2-{7-[(Methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide The procedure is as in Example 80, but the ammonium hydroxide in Step C is replaced by methylamine.
- 68 Melting point = 155-156*C By proceeding as in Example 80, but replacing, in Step A, the compound of Preparation 1 by the appropriate substrate, and, in Step C, the ammonium hydroxide by the appropriate amine, Examples 82 to 84 are obtained: 5 EXAMPLE 82: N-(2-{7-[(Methylamino)sulphonyl]-1-naphthyl}ethyl)-2-furamide Starting compound: Preparation 135 EXAMPLE 83 : N-(2-{7-[(Ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide Starting compound : Preparation 136 EXAMPLE 84 : N-(2-{7-[(Methylamino)sulphonyl]-1-naphthyl}ethyl)cyclopropane 10 carboxamide Starting compound: Preparation 137 EXAMPLE 85: N-(3-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}propyl)acetamide Starting compound: Preparation 16 EXAMPLE 86: N-(2-{5-[(Propylamino)sulphonyll-1-benzofuran-3-ylethyl)acetamide 15 Starting compound: Preparation 18 EXAMPLE 87 : N-(2-{5-[(Cyclopropylamino)sulphonyl]-1-benzofuran-3-yl}ethyl) benzamide Starting compound: Preparation 138 EXAMPLE 88: N-(2-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-2-furamide 20 Starting compound: Preparation 139 EXAMPLE 89 : N-(2-{5-[(Hexylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropane carboxamide Starting compound: Preparation 140 ST, -7 - 69 EXAMPLE 90 : N-(2-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl)ethyl)cyclopropane carboxamide Starting compound: Preparation 140 EXAMPLE 91 : N-(2-{2-Benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl ethyl) 5 acetamide Starting compound: Preparation 19 EXAMPLE 92: N-(2-{5-[(Isopropylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl) cyclopropanecarboxamide Starting compound: Preparation 141 10 EXAMPLE 93: N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl) acetamide Starting compound: Preparation 142 EXAMPLE 94: N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl) cyclopropanecarboxamide 15 Starting compound: Preparation 143 EXAMPLE 95: N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl) benzamide Starting compound: Preparation 144 EXAMPLE 96: N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl) 20 2-furamide Starting compound: Preparation 145 Examples 97 to 105 are obtained by proceeding as in Example 1, but replacing the acid chloride by the corresponding halogenocarboxylate. ST S -X - 70 EXAMPLE 97: Methyl 5-[(acetylamino)methyl-2,3-dihydro-1,4-benzodioxin-6-yl carbamate Starting compound: Preparation 126 EXAMPLE 98 : Methyl 3-[(acetylamino)methyl]-3,4-dihydro-2H-chromen-6-yl-carbamate 5 Starting compound: Preparation 124 EXAMPLE 99 : Ethyl 3-[2-(acetylamino)ethyl]-2,3-dihydro-1H-inden-5-yl-carbamate Starting compound: Preparation 134 EXAMPLE 100 : Methyl 3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl carbamate 10 Starting compound: Preparation 148 EXAMPLE 101 : Methyl 3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl carbamate Starting compound: Preparation 151 EXAMPLE 102: Methyl 3-[2-(benzoylamino)ethyl]-1H-pyrrolo[ 2
,
3 -bpyridin-5-yl 15 carbamate Starting compound: Preparation 154 EXAMPLE 103: Methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl)-1H-pyrrolo[2,3-b] pyridin-5-yl-carbamate Starting compound: Preparation 157 20 EXAMPLE 104: Methyl 3-{2-[(cyclopropylcarbonyl)aminolethyl}-1H-pyrrolo[3,2-b] pyridin-5-yl-carbamate Starting compound: Preparation 161 EXAMPLE 105: Ethyl 3-[2-(acetylamino)ethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl-carbamate Starting compound: Preparation 165 7z -71 Examples 106 to 108 are obtained by proceeding as in Example 1, starting from the appropriate substrate. EXAMPLE 106: N-{8-[2-(Acetylamino)ethyl]-2-naphthyl}acetamide Starting compound: Preparation 117 5 EXAMPLE 107: N-{2-[5-(Acetylamino)-1-benzofuran-3-yl ethyl}cyclopropane carboxamide Starting compound: Preparation 168 EXAMPLE 108: N-{2-[5-(Acetylamino)-1-benzothiophen-3-ylethyl}benzamide Starting compound :Preparation 172 10 Examples 109 to 112 are obtained by proceeding as in Preparation 109, condensing the appropriate amine with the intermediate acid chloride. EXAMPLE 109: 3-[2-(Acetylamino)ethyl]-N-methyl-H-pyrrolo[2,3-blpyridine-5 carboxamide Starting compound: Preparation 147 15 EXAMPLE 110: N-(2-{7-[(Methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide Starting compound: Preparation 174 EXAMPLE 111: 3-{2-[(Cyclopropylcarbonyl)aminolethyl}-N-ethyl-1-benzofuran-5 carboxamide Starting compound: Preparation 167 20 EXAMPLE 112: 3-[2-(Benzoylamino)ethyl]-N-ethyl-1-benzofuran-5-carboxamide Starting compound: Preparation 176 - 72 EXAMPLE 113: N-{8-[2-(Acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}acetamide Step A : 7-Nitro-3,4-dihydro-1(2H)-naphthalenone 7 mmol of 1-oxo-1,2,3,4-tetrahydronaphthalene and 5 ml of concentrated sulphuric acid are cooled in a freezer for 30 minutes. The reaction mixture is then placed in a bath of alcohol at 5 -15'C on a cooling plate. A sulphonitric mixture (1.1 ml of sulphuric acid and 0.73 ml of nitric acid) is prepared and brought to the temperature of the reaction mixture before being added dropwise, avoiding any drastic heating of the mixture. Stirring is carried out for 15 minutes and then hydrolysis on a pile of ice is carried out. The pale yellow precipitate obtained is washed with water until the washing waters have a neutral pH and is then dried in a desiccator and 10 purified on a silica gel column. Melting point = 103.7-104.3*C Step B: 2-[7-Nitro-3,4-dihydro-1(2H)-naphthalenylidene]acetonitrile Using a 50 ml two-necked flask under a current of nitrogen and placed in a bath of alcohol at -15*C, 0.32 g of sodium hydride is added in portions to 40 ml of THF, with magnetic stirring, 15 and then 1.4 g of diethyl cyanomethylphosphonate in 10 ml of THF are added dropwise. After stirring for half an hour, when the mixture is highly homogeneous, the flask is plunged into a medium at -78*C (cryostat), and 1 g of the compound obtained in Step A, dissolved in 20 ml of THF, is added dropwise. Stirring under a current of nitrogen is carried out for 2 hours. The reaction mixture is then brought to ambient temperature, hydrolysed on ice and precipitated. 20 After filtering under suction and washing with water until the washing waters have a neutral pH, extraction with 3 volumes of ether is carried out. The organic phases are washed with 3 volumes of water and then dried. The grey solid obtained is decolorised on carbon. Melting point = 98.1-98.5*C Step C: N-{8-[2-(Acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}acetamide 25 9 mmol of the compound obtained in Step B are dissolved in acetic anhydride (100 ml) and then _a small spatula of sodium acetate is added. The mixture is introduced into an autoclave, Raney -73 nickel is added and autoclaving under a pressure of 40 bars is carried out for 6 hours, with stirring at 50-60*C. The mixture is filtered and is rinsed with alcohol at 95*C; the solvent is then evaporated off. Hydrolysis is carried out using 100 ml of distilled water and extraction with 3 volumes of dichloromethane is carried out. The organic phase is washed with 2 volumes of 5 water, dried over magnesium sulphate, filtered and evaporated. Rinsing with an ether/dichloromethane mixture and trituration in ether are carried out. The light-beige solid obtained is recrystallised. Melting point = 127.7-128.7'C Elemental microanalysis: 10 C H N % calculated: 70.04 8.08 10.21 %found: 69.74 8.14 10.43 EXAMPLE 114: Methyl 8-[2-(acetylamino)ethyll-2-naphthyl-carbamate The procedure is as in Example 97. 15 Starting compound : Preparation 117 EXAMPLE 115: N-[2-(1,3-Dioxo-1,2,3,4-tetrahydrobenzoVt]quinolin-10-yl)ethyl]-2-phenyl acetamide A solution of the product obtained in Preparation 109 (10 mmol) in ether (160 ml) is added very slowly, using a dropper, to a solution of malonyl dichloride (40 mmol) in ether (40 ml) and 20 triethylamine (2 ml). At the end of the reaction, the reaction mixture is concentrated under reduced pressure. The residue is dried using a vane pump and then taken up in ether. The organic phase is washed with water, dried over magnesium sulphate, concentrated under reduced pressure and then dried using a vane pump. The residue is then taken up in 100 ml of 1,1,2,2 tetrachloroethane. The resulting solution is then added dropwise to a solution of aluminium 25 chloride (30 mmol) in 50 ml of the same solvent under nitrogen. The mixture is heated at 60*C until the reaction has ceased; the reaction mixture is then poured into a mixture of ice (20 g) and concentrated HCl (1 ml) and is stirred for one hour. The aqueous phase is extracted twice with chloroform and then the combined organic phases are dried over magnesium sulphate and -7 z -74 concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title product. In Examples 116 to 120 the procedure is as in Example 115, starting from appropriate substrates. EXAMPLE 116: N-Cyclohexyl-4-(1,3-dioxo-1,2,3,4-tetrahydrobenzo[f1quinolin-10-yl) 5 butanamide Starting compound: Preparation 112 EXAMPLE 117: N-[2-(7-Benzoyl-1,2-dioxo-2,3-dihydro-1H-benzo[e]indol-9-yl)ethyl]-N' propylurea Starting compound: Preparation 115 10 EXAMPLE 118: N-Methyl-4-(7,9-dioxo-6,7,8,9-tetrahydrofuro[3,2-A quinolin-1-yl) butanamide Starting compound: Preparation 119 EXAMPLE 119: N-{2-[2-(4-Fluorobenzyl)-3-methyl-7,8-dioxo-3,6,7,8-tetrahydro dipyrrolo [2,3-b:3,2-d pyridin-1-yllethyl}acetamide 15 Starting compound: Preparation 122 EXAMPLE 120: N-[(8,10-Dioxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-Aquinolin-2-yl) methyllacetamide Starting compound: Preparation 124 EXAMPLE 121 : N-[2-(3-Oxo-1,2,3,4-tetrahydrobenzo [fquinolin-10-yl)ethyl]-2-phenyl 20 acetamide The product of Example 115 (3 mmol) is dissolved in acetic acid (70 ml). After several purges with argon, 10 % palladium-on-carbon (600 mg) is added and the mixture is placed under a hydrogen atmosphere. Stirring is carried out at ambient temperature until the end of the reaction S -7 -75 (monitored by TLC) and the palladium is filtered off over Celite. The acetic acid is evaporated off to dryness and the residue is chromatographed on silica gel to yield the title product. In Examples 122 to 126 the procedure is as in Example 121, starting from appropriate substrates. EXAMPLE 122: N-Cyclohexyl-4-(3-oxo-1,2,3,4-tetrahydrobenzo[11quinolin-10-yl) 5 butanamide Starting compound: Example 116 EXAMPLE 123: N-[2-(7-Benzoyl-2-oxo-2,3-dihydro-1H-benzo[eindol-9-yl)ethyl]-N' propylurea Starting compound : Example 117 10 EXAMPLE 124: N-Methyl-4-(9-oxo-6,7,8,9-tetrahydrofuro[3,2-f]quinolin-1-yl) butanamide Starting compound: Example 118 EXAMPLE 125: N-{2-[2-(4-Fluorobenzyl)-3-methyl-8-oxo-3,6,7,8-tetrahydropyrrolo [2,3-b:3,2-d pyridin-1-yl]ethyl}acetamide 15 Starting compound: Example 119 EXAMPLE 126: N-[(8-Oxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-f1quinolin-2-yl) methyl]acetamide Starting compound : Example 120 EXAMPLE 127: N-[2-(4-Oxo-3,4-dihydrobenzo[f]isoquinolin-10-yl)ethyl]-1-cyclohexane 20 carboxamide The product of Example 33 (10 mmol) and triethylene glycol are introduced into a two-necked flask. Heating is carried out at 160-170*C, under nitrogen and with stirring, for five hours. The reaction mixture is poured into ice-cold water and is extracted with ethyl acetate. The organic S 9$ e is washed with water and dried over calcium chloride. After filtration, the organic phase is 7 -76 concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title product. In Examples 128 to 132, the procedure is as in Example 127, starting from appropriate substrates. 5 EXAMPLE 128: N-12-(2-Benzyl-7-isopropyl-6-oxo-6,7-dihydrothieno[3,2-A isoquinolin-1 yl)ethyl]acetamide Starting compound: Example 37 EXAMPLE 129: N-[2-(3-Cyclohexyl-4-oxo-3,8,9,10-tetrahydro-4H-thiopyrano[3,2-f] isoquinolin-10-yl)ethyl]acetamide 10 Starting compound: Example 40 EXAMPLE 130: N-[2-(4-Oxo-3,4-dihydrobenzo[]isoquinolin-10-yl)ethyll-2-bromo acetamide Starting compound: Example 46 EXAMPLE 131: N-12-(2-Benzyl-6-oxo-6,7-dihydrofuro[3,2-fJisoquinolin-1-yl)ethy1-1 15 cyclopropanecarboxamide Starting compound: Example 49 EXAMPLE 132: N-[(9-Isopropyl-7-oxo-3-phenyl-3,7,8,9-tetrahydrochromeno[6,5-c] azepin-2-yl)methyllbutanamide Starting compound: Example 50 - 77 EXAMPLE 133: N-[2-(1,4-Dioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-Aisoquinolin-10 yl)ethyl]-2-phenylacetamide Step A : 2-{[(4-{2-[(2-Phenylacetyl)amino]ethyl}-3,4-dihydro-2H-chromen-6-yl) carbonyl]amino} acetic acid 5 A 0.5N aqueous solution of K 2 C0 3 (10 ml) is added to the product obtained in Example 39 (4 mmol) dissolved in methanol (10 ml). When the reaction has ceased, the solution is acidified to pH 6-7 using IN hydrochloric acid solution. The reaction mixture is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the 10 title product. Step B: 2-{[(4-{2-[(2-Phenylacetyl)amino]ethyl}-3,4-dihydro-2H-chromen-6-yl) carbonyl]amino} acetyl chloride The product obtained in Step A (3 mmol), dissolved in thionyl chloride, is stirred at 60'C under a current of nitrogen for one hour. The thionyl chloride is evaporated off under reduced pressure 15 and the residue is dried with the aid of a vane pump to yield the title product. Step C: N-[2-(1,4-Dioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl) ethyl]-2-phenylacetamide The product obtained in Step B (3 mmol), dissolved in 1,1,2,2-tetrachloroethane (30 ml), is added dropwise to a solution of aluminium chloride (10 mmol) in the same solvent (20 ml) under 20 nitrogen. The reaction mixture is heated at 60*C, with stirring, until the reaction has ceased. The solution is then poured into a mixture of ice (10 g) / concentrated HCl (0.3 ml) and stirring is carried out for one hour. The aqueous phase is extracted twice with chloroform; the combined organic phases are then dried over magnesium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title product. n Examples 134 to 135 the procedure is as in Example 133, starting from appropriate reactants. 7 2 - 78 EXAMPLE 134: N-[2-(1,4-Dioxo-8-naphthyl-1,2,3,4-tetrahydro[/]isoquinolin-10-yl) ethyl] heptanamide Starting compound: Example 45 EXAMPLE 135: N-{2-[8-(Cyclopropylmethyl)-1,4-dioxo-1,2,3,4-tetrahydrobenzo[/] 5 isoquinolin-10-yll ethyl) acetamide Starting compound: Example 48 In Examples 136 to 138 the procedure is as in Example 122, starting from appropriate substrates. EXAMPLE 136: N-[2-(4-Oxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-flisoquinolin-10-yl) ethyl]-2-phenylacetamide 10 Starting compound: Example 133 EXAMPLE 137: N-[2-(4-Oxo-8-naphthyl-1,2,3,4-tetrahydrobenzo[fisoquinolin-10-yl) ethyl] heptanamide Starting compound: Example 134 EXAMPLE 138: N-{2-[8-(Cyclopropylmethyl)-4-oxo-1,2,3,4-tetrahydrobenzof] 15 isoquinolin-10-yllethyl}acetamide Starting compound: Example.135 EXAMPLE 139: N-[2-(4-Thioxo-3,4-dihydrobenzo[1]isoquinolin-10-yl)ethyl]-1 cyclohexanecarbothioamide The product obtained in Example 127 is treated with Lawesson's reagent to yield the title 20 compound. Examples 140 to 142 are obtained by proceeding as in Example 139. EXAMPLE 140: N-[2-(3-Cyclohexyl-4-thioxo-3,8,9,10-tetrahydro-4H-thiopyrano[3,2-A isoquinolin-10-yl)ethyllacetamide 1 1 Starting compound: Example 129 - 79 EXAMPLE 141: N-[2-(1,4-Dithioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-A isoquinolin 10-yl)ethyl]-2-phenylethanethioamide Starting compound: Example 133 EXAMPLE 142: N-{2-[8-(Cyclopropylmethyl)-4-thioxo-1,2,3,4-tetrahydrobenzo[/] 5 isoquinolin-10-yl] ethyl}ethanethioamide Starting compound: Example 138 EXAMPLE 143: N-Cyclohexyl-4-(1-hydroxy-3-oxo-1,2,3,4-tetrahydrobenzoV/]quinolin-10 yl)butanamide A solution of the product obtained in Example 116 (2 mmol) dissolved in methanol (10 ml) is 10 added dropwise to a suspension of sodium hydride (2.2 mmol) in methanol (50 ml) at -40*C. Stirring is carried out until the starting compound has completely disappeared (about 3 hours). At the end of the reaction, the solution is poured into water (30 ml). The reaction mixture is concentrated under reduced pressure to a volume of about 30 ml and is then extracted with ethyl acetate. The aqueous phase is washed with water, dried over magnesium sulphate and 15 concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title product. In Examples 144 and 145, the procedure is as in Example 143. EXAMPLE 144: N-[(10-Hydroxy-8-oxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-A quinolin 2-yl)methyllacetamide 20 Starting compound: Example 120 EXAMPLE 145: N-[2-(1-Hydroxy-4-methyl-1,2,3,4-tetrahydrobenzol]quinolin-10 yl)ethyl]-2-phenylacetamide Starting compound: Example 133 QS T - 80 EXAMPLE 146: Methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate The procedure is as in Examples 74 and 75. EXAMPLE 147: Methyl 3-{2-[(cyclopentylcarbonyl)amino] ethyl}-1-benzofuran-5-yl carbamate 5 The procedure is as in Examples 74 and 75. EXAMPLE 148: Methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate The procedure is as in Example 63. EXAMPLE 149: Methyl 3-[2-(isobutylamino)ethyl]-benzofuran-5-carboxylate The procedure is as in Example 63. 10 EXAMPLE 150: 3-[2-(Benzoylamino)ethyl]-1-benzofuran-5-carboxamide The procedure is as in Example 67. EXAMPLE 151 : Methyl 8-[2-(3-butenoylamino)ethyl]-2-naphthyl-carbamate The procedure is as in Examples 74 and 75. EXAMPLE 152: N-{8-[2-(Acetylamino)ethyl]-2-naphthyl}-4-fluorobenzamide 15 The procedure is as in Example 1, starting from the compound obtained in Preparation 117. EXAMPLE 153: Ethyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate The procedure is as in Example 62.
-81 PHARMACOLOGICAL STUDY EXAMPLE A: Acute toxicity study Acute toxicity was evaluated after oral administration to groups each comprising 8 mice (26 1 2 grams). The animals were observed at regular intervals during the course of the first day, 5 and daily for the two weeks following treatment. The LD 5 0 (dose that causes the death of 50% of the animals) was evaluated and demonstrated the low toxicity of the compounds of the invention. EXAMPLE B : Melatonin receptor binding study on pars tuberalis cells of sheep Melatonin receptor binding studies of the compounds of the invention were carried out according to conventional techniques on pars tuberalis cells of sheep. The pars tuberalis of the 10 adenohypophysis is in fact characterised in mammals by a high density of melatonin receptors (Journal of Neuroendocrinology, 1, pp. 1-4, 1989). Protocol 1) Sheep pars tuberalis membranes are prepared and used as target tissue in saturation experiments to determine the binding capacities and affinities for 2-[ 12 5 1]-iodomelatonin. 15 2) Sheep pars tuberalis membranes are used as target tissue in competitive binding experiments using the various test compounds in comparison with melatonin. Each experiment is carried out in triplicate and a range of different concentrations is tested for each compound. The results enable the determination, after statistical processing, of the binding affinities of the compound tested. S Tjy - 82 Results The compounds of the invention appear to have a strong affinity for melatonin receptors. EXAMPLE C: 1. Melatonin mt, and MT 2 receptor binding study The mt, or MT 2 receptor binding experiments are carried out using 2-[' 2 1]-melatonin as reference 5 radioligand. The radioactivity retained is determined using a liquid scintillation counter. Competitive binding experiments are then carried out in triplicate using the various test compounds. A range of different concentrations is tested for each compound. The results enable the binding affinities of the compounds tested (IC 50 ) to be determined. 2. Study of binding to MT. melatonin binding sites 10 The MT3 site binding experiments are carried out on hamster brain membranes using 2-['I] melatonin as reference radioligand. The membranes are incubated for 30 minutes with the 2 [ 2 1]-melatonin at a temperature of 4*C and at different concentrations of the test compounds. After incubation, the membranes are quickly filtered and then washed with cold buffer using a filtration system. The radioactivity fixed is measured using a scintillation counter. The IC 50 5 values (concentration inhibiting specific binding by 50 %) are calculated from competition curves according to a non-linear regression model. The IC 5 0 values found for the compounds of the invention demonstrate binding to one or other of the receptor sub-types, the values being < 10piM. EXAMPLE D : Action of the compounds of the invention on the circadian rhythms of 20 locomotive activity of the rat The involvement of melatonin in influencing, by day/night alternation, the majority of physiological, biochemical and behavioural circadian rhythms has made it possible to establish a Toc' pharmacological model for research into melatoninergic ligands. 7 z -83 The effects of the molecules are tested on numerous parameters and, in particular, on the circadian rhythms of locomotive activity, which are a reliable indicator of the endogenous circadian clock. In this study, the effects of such molecules on a particular experimental model, namely the rat 5 placed in temporal isolation (permanent darkness), is evaluated. Experimental protocol One-month-old male rats are subjected, as soon as they arrive at the laboratory, to a light cycle of 12 hours' light per 24 hours (LD 12 : 12). After 2 to 3 weeks' adaptation, they are placed in cages fitted with a wheel connected to a 10 recording system, in order to detect the phases of locomotive activity and thus monitor the nychthemeral rhythms (LD) or circadian rhythms (DD). As soon as the rhythms recorded show a stable pattern during the light cycle LD 12 : 12, the rats are placed in permanent darkness (DD). Two to three weeks later, when the free course (rhythm reflecting that of the endogenous clock) 5 is clearly established, the rats are given a daily administration of the molecule to be tested. The observations are made by means of visualisation of the rhythms of activity: - influence on the rhythms of activity by the light/dark cycle, - disappearance of the influence on the rhythms in permanent darkness, - influence on the activity by the daily administration of the molecule; transitory or durable 20 effect. A software package makes it possible: S z - 84 - to measure the duration and intensity of the activity, the period of the rhythm of the animals during free course and during treatment, - possibly to demonstrate by spectral analysis the existence of circadian and non-circadian (for example ultradian) components. 5 Results The compounds of the invention clearly appear to allow powerful action on the circadian rhythm via the melatoninergic system. EXAMPLE E : Light/dark cages test The compounds of the invention are tested on a behavioural model, the light/dark cages test, 10 which allows the anxiolytic activity of the compounds to be demonstrated. The apparatus consists of two polyvinyl boxes covered with Plexiglass. One of the boxes is in darkness. A lamp is placed above the other box, yielding a light intensity of approximately 4000 lux in the centre of the box. An opaque plastic tunnel separates the light box from the dark box. The animals are tested individually for a session of 5 minutes. The floor of each box is 15 cleaned between each session. At the start of each test, the mouse is placed in the tunnel, facing the dark box. The time spent by the mouse in the illuminated box and the number of passages through the tunnel are recorded after the first entry into the dark box. After administration of the compounds 30 minutes before the start of the test, the compounds of the invention significantly increase the time spent in the illuminated cage and the number of 20 passages through the tunnel, which demonstrates the anxiolytic activity of the compounds of the invention. EXAMPLE F : Activity of compounds of the invention on the caudal artery of the rat The compounds of the invention were tested in vitro on the caudal artery of the rat. S T atoninergic receptors are present in those vessels, thus providing a relevant pharmacological 7 -85 model for studying melatoninergic ligand activity. The stimulation of the receptors can cause either vasoconstriction or dilation depending on the arterial segment studied. Protocol One-month old rats are accustomed to a light/dark cycle of 12h/12h during a period of 2 to 3 5 weeks. After sacrifice, the caudal artery is isolated and maintained in a highly oxygenated medium. The arteries are then cannulated at both ends, suspended vertically in an organ chamber in a suitable medium and perfused via their proximal end. The pressure changes in the perfusion flow enable evaluation of the vasoconstrictive or vasodilatory effect of the compounds. 10 The activity of the compounds is evaluated on segments that have been pre-contracted by phenylephrine (1pM). A concentration/response curve is determined non-cumulatively by the addition of a concentration of the test compound to the pre-contracted segment. When the observed effect reaches equilibrium, the medium is changed and the preparation is left for 20 minutes before the addition of the same concentration of phenylephrine and a further 15 concentration of the test compound. Results The compounds of the invention significantly modify the diameter of caudal arteries pre constricted by phenylephrine. EXAMPLE G : Pharmaceutical composition: tablets 20 1000 tablets each comprising 5 mg of methyl 3-{2-[(cyclopropylcarbonyl) amino]ethyl} -1 -benzofuran-5-yl-carbamate (Example 75).............................. 5 g w heat starch ...................................................................................................... 20 g m aize starch ...................................................................................................... 20 g lactose ............................................................................................................... 30 g 25 m agnesium stearate ......................................................................................... 2 g silica ................................................................................................................. I g hydroxypropyl cellulose................................................................................... 2 g

Claims (71)

1. Compound of formula (I): R-A-R' (I) wherein: 5 + A represents: - a ring system of formula (II): -~y (II) wherein e X represents an oxygen, sulphur or nitrogen atom or a group C(H)q (wherein q is 0, 1 or 2) or NRO (wherein R represents a hydrogen atom, a linear or branched 10 (C,-C 6 )alkyl group, an aryl group, an aryl-(C,-C 6 )alkyl group in which the alkyl moiety is linear or branched) or SO 2 Ph, " Y represents a nitrogen atom or a group C(H)q (wherein q is 0, 1 or 2), " Z represents a nitrogen atom or a group C(H)q (wherein q is 0, 1 or 2), but X, Y and Z cannot represent three hetero atoms simultaneously, 15 e B represents a benzene or pyridine nucleus, * the symbol .. means that the bonds may be single or double, it being understood that the valency of the atoms is respected, wherein R substitutes the ring B and R' substitutes the ring containing the groups X, Y and Z, or R and R' substitute the ring B, 20 - a ring system of formula (III): '(III) wherein e X' represents an oxygen or sulphur atom or a group C(H)q (wherein q is 0, 1 or 2), - 87 " Y' represents a group C(H), (wherein q is 0, 1 or 2) or NR wherein R is as defined hereinbefore, " Z' represents a group C(H)q (wherein q is 0, 1 or 2) or NRO wherein R 0 is as defined hereinbefore, 5 * T' represents an oxygen or sulphur atom or a group C(H)q (wherein q is 0, 1 or 2), it being understood that, when Y' or Z' represents a hetero atom, the other three variables ((X', Z', T') and (X', Y', T'), respectively) cannot represent a hetero atom, e the symbol. is as defined hereinbefore, 10 e B' represents: * a benzene nucleus, * a naphthalene nucleus when X', Y', Z' and T' do not simultaneously represent a group C(H)q (wherein q is 0, 1 or 2), * or a pyridine nucleus when X' and T' simultaneously 15 represent a group C(H)q (wherein q is 0, 1 or 2), wherein R substitutes the ring B' and R' substitutes the ring containing the groups X', Y', Z' and T', or R and R' substitute the ring B', - a ring system of formula (IV): )n (IV) D 20 representing the ring systems (IV.): - 88 / W W (IVa) (IVb) (IVc) (IVd) wherein. n is an integer such that 0 n 3, W represents an oxygen, sulphur or nitrogen atom, or a group [C(H),]p (wherein q is 0, 1 or 2, and p is 1 or 2) or NRO wherein R 0 is as defined 5 hereinbefore, e the symbol .. is as defined hereinbefore, wherein R' substitutes the ring )n and R substitutes one or other of the two other rings, - or a biphenyl group wherein R substitutes one of the benzene rings and R' substitutes the 10 other, or R and R' substitute the same benzene ring, it being understood that the ring systems of formulae (II), (III) and (IV) and the biphenyl group may be unsubstituted or substituted (in addition to the substituents R and R') by from 1 to 6 radicals, which may be the same or different, selected from Ra, OR, COR., COOR,, OCORa, OSO 2 CF 3 and halogen atoms, 15 wherein R, represents a hydrogen atom, an unsubstituted or substituted linear or branched (C 1 -C 6 )alkyl group, an unsubstituted or substituted linear or branched (C 2 -C 6 )alkenyl group, an unsubstituted or substituted linear or branched (C 2 -C 6 )alkynyl group, a linear or branched (C-C 6 )polyhaloalkyl group, an unsubstituted or substituted (C 3 -C)cycloalkyl group, an unsubstituted or substituted (C 3 C)cycloalkyl-(C-C 6 )alkyl group in which the 20 alkyl group is linear or branched, an unsubstituted or substituted (C 3 -Cg)cycloalkenyl group, an unsubstituted or substituted (C 3 C,)cycloalkenyl-(C-C 6 )alkyl group in which the alkyl group is linear or branched, an aryl group, an aryl-(C-C 6 )alkyl group in which the alkyl moiety is linear or branched, an aryl-(C-C 6 )alkenyl group in which the alkenyl - 89 moiety is linear or branched, a heteroaryl group, a heteroaryl-(C,-C 6 )alkyl group in which the alkyl moiety is linear or branched, a heteroaryl-(C-C 6 )alkenyl group in which the alkenyl moiety is linear or branched, an unsubstituted or substituted linear or branched (Cl-C 6 )heterocycloalkyl group, an unsubstituted or substituted heterocycloalkenyl group, a 5 substituted or unsubstituted heterocycloalkyl-(C-C 6 )alkyl group in which the alkyl moiety is linear or branched, or a substituted or unsubstituted heterocycloalkenyl-(C-C 6 )alkyl group in which the alkyl moiety is linear or branched, + R represents : - a group of formula (V): -C-R II (V) 10 wherein o Q represents a sulphur or oxygen atom, e R1 represents a group NR'aR". or OR'a (wherein R'a and R"a, which may be the same or different, may take any of the values of R. and may also form, together with the nitrogen atom carrying them, a 5- to 10-membered cyclic group which 15 may contain, in addition to the nitrogen atom by which it is linked, from one to three hetero atoms selected from oxygen, sulphur and nitrogen, and R'a may take any of the values of Ra except for the hydrogen atom), - a group of formula (VI): ,2 -N (VI) R 20 wherein e R 2 represents a group R. as defined hereinbefore, * R 3 represents a group COR'a, CSR'a, CONR'aR"a, CSNR'aR"a, COOR'a, CSOR'a or S(O),R'a (wherein R'a and R"a, which may be the same or different, are as defined hereinbefore and may also form, together with the nitrogen atom carrying them, a cyclic group as defined hereinbefore, and v is 1 or 2), 25 - a group of formula (VII): S 7 -90 -S-R4 (VII) (O), wherein v is as defined hereinbefore and R represents a group NR'aR"a, NRaCOR'a, NR.CSR'a, NRaCONR'aR"a, NRaCSNR'aR"a or NRaCOOR'a, wherein Ra, R'a and R"a are as defined hereinbefore, 5 - or, when A represents a ring system of formula (II) or (III) or a biphenyl group, forms, together with two adjacent carbon atoms of the cyclic structure A carrying it, a ring of formula (VIII): (VIII) A (O), (O), Q Ra Ra I 1 1| 1 1 whereinErepresentsagroup -S-N- , -S-N-C- , -N-S- , -N-C I 1 I 1 Fla ( Qv a aa Q Ial IaI -N-C-O- , -N-C-N-, -C-N- or -C-0--whereinr,Q,Ra,R'a || II l | Il 10 Q Q and v are as defined hereinbefore, the ring formed containing from 5 to 7 atoms and it being possible for the said ring to contain from 1 to 3 hetero atoms selected from nitrogen, sulphur and oxygen, and one or more unsaturations, and being optionally substituted by one or more radicals, which may be the 15 same or different, selected from R., OR, CORa, COORa, OCORa, NR'aR"a, NR.COR'a, CONR'aR"a, cyano, oxo, SR., S(O)R,, SO 2 R, CSRa, NRCSR'a, CSNR'aR"a, NR.CONR'aR"a, NR.CSNR'aR"a and halogen atoms, -91 wherein R, R'a and R"a, which may be the same or different, are as defined hereinbefore and R'a and R"a may also form, together with the nitrogen atom carrying them, a cyclic group as defined hereinbefore, + and R' represents a group of formula (IX): - G -RS (IX) 5 wherein * G represents an alkylene chain -(CH 2 ):- (wherein t is an integer such that 0 t 4 when A represents a tricyclic structure and such that 1 t 5 4 when A represents a bicyclic structure), optionally substituted by one or more radicals, which may be the same or different, selected from R., OR,, COOR., CORa, (in which Ra is as 10 defined hereinbefore) or halogen atoms, R R I a I a 9 and R 5 represents a group -N-C-R'a , -N-C-NR'aR'a , -C-NR'aR"a R Q Q Ra or -O-1-C-R' wherein Q, Ra, R'a and R"a (which may be the same or different) ||C a Q are as defined hereinbefore, it being possible for R'a and R"a to form, together with the nitrogen atom carrying them, a cyclic group as defined hereinbefore, 15 it being understood that: - "heterocycloalkyl" is taken to mean any saturated mono- or poly-cyclic group containing from 5 to 10 atoms containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur, - "heterocycloalkenyl" is taken to mean any non-aromatic mono- or poly-cyclic group 20 containing one or more unsaturations, containing from 5 to 10 atoms and which may contain from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur, - the term "substituted" used in respect of the expressions "alkyl", "alkenyl" and "alkynyl" indicates that the groups in question are substituted by one or more radicals, rs _ -92 which may be the same or different, selected from hydroxy, linear or branched (C,-C 6 )alkoxy, linear or branched (C 1 -C 6 )alkyl, linear or branched (C,-C 6 )polyhaloalkyl, amino and halogen atoms, - the term "substituted" used in respect of the expressions "cycloalkyl", "cycloalkylalkyl", 5 "cycloalkenyl", "cycloalkenylalkyl", "heterocycloalkyl", "heterocycloalkenyl", "hetero cycloalkylalkyl" and "heterocycloalkenylalkyl" indicates that the cyclic moiety of the groups in question is substituted by one or more radicals, which may be the same or different, selected from hydroxy, linear or branched (Cl-C 6 )alkoxy, linear or branched (C 1 -C 6 )alkyl, linear or branched (Cl-C 6 )polyhaloalkyl, amino and halogen atoms, 10 - "aryl" is taken to mean any aromatic, mono- or poly-cyclic group containing from 6 to 22 carbon atoms, and also the biphenyl group, - "heteroaryl" is taken to mean any aromatic mono- or poly-cyclic group containing from 5 to 10 atoms containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur, 15 it being possible for the "aryl" and "heteroaryl" groups to be substituted by one or more radicals, which may be the same or different, selected from hydroxy, linear or branched (Cl-C 6 )alkoxy, linear or branched (C 1 -C 6 )alkyl, linear or branched (C 1 -C 6 )polyhaloalkyl, cyano, carboxy, nitro, amino and halogen atoms, it being understood that : 20 - when A represents an indole nucleus, there cannot be any substituents in the 2-position, - when A represents an indole nucleus and R represents a group -NHCOR',, -NHCOOR', or NHCONR'aR"a, then G-R cannot represent a group -(CH 2 ) 2 -NHCORb wherein Rb represents a (C 1 -C 4 )alkyl or CF 3 group, - when A represents a benzofuran or benzothiophene nucleus, there cannot be any COPh 25 groups (wherein Ph is substituted or unsubstituted) in the 2-position, - 93 - when A represents a benzofuran or benzothiophene nucleus, R cannot represent a group -NRaCOR, -NHSO 2 R., -NHCOCH 2 R, or NHCONHR, wherein R. represents a heterocyclic or aryl group, - when A represents a tetrahydronaphthalene group, R cannot represent a group 5 CONR'aR"a, - when A represents a hydrocarbon ring system and R represents a group NHCOR'a, then R cannot represent a group COOR'a, - the compound of formula (I) cannot represent: * N-{8-[(acetylamino)methyl]-2-naphthyl}-2-methylpropanamide, 10 e N-(2-{5-[(4-ethoxyanilino)sulphonyl]-1H-indol-3-yl}ethyl)acetamide, " 8-[(acetylamino)methyl]-N-isopropyl-2-naphthamide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
2. Compounds of formula (I) according to claim 1, wherein A represents a ring system of 15 formula (II') 4 5 3 B (II') 62 wherein B, X and the symbol . are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
3. Compounds of formula (I) according to claim 1, wherein A represents a ring system of 20 formula (III'): (III') 5 4 wherein B', X', T' and the symbol . are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. S - 94
4. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (II') substituted in the 5-position by a group R as defined in claim 1 and in the 3 position by a group R' as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
5 5. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (III') substituted in the 7-position by a group R as defined in claim 1 and in the 1- or 2-position by a group R' as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
6. Compounds of formula (I) according to claim 1, wherein R represents a group of io formula (V), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
7. Compounds of formula (I) according to claim 1, wherein R represents a group of formula (VI), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 15
8. Compounds of formula (I) according to claim 1, wherein R represents a group of formula (VII), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
9. Compounds of formula (I) according to claim 1, wherein R represents a group of formula (V) wherein Q represents an oxygen atom and R' represents a group NR'aR"a as 20 defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
10. Compounds of formula (I) according to claim 1, wherein R represents a group of formula (V) wherein Q represents an oxygen atom and R' represents a group OR'a as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a 25 pharmaceutically acceptable acid or base. 0S - 95
11. Compounds of formula (I) according to claim 1, wherein R represents a group of formula (VI) wherein R 3 represents a group COR'a wherein R'a is as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 5
12. Compounds of formula (I) according to claim 1, wherein R represents a group of formula (VI) wherein R' represents a group COOR'a wherein Ra is as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
13. Compounds of formula (I) according to claim 1, wherein R represents a group of 10 formula (VII) wherein v is 2 and R represents a group NR'aNR"a, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
14. Compounds of formula (I) according to claim 1, wherein R' represents a group G-R wherein G represents an unsubstituted or substituted alkylene chain -(CH 2 ),- wherein t is 2 or 3 and Ra Ra R 5 represents a group -N-C-Ra , -N-C-NR'aR"a or -C-NR aR" wherein Q Q Q 15 Ra, R'a, R"a and Q are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
15. Compounds of formula (I) according to claim 1, wherein R' represents a group G-R wherein G represents an alkylene chain -(CH 2 ),- wherein t is 2 or 3 and R5 represents a group -NHCOR'a or -CONHR'a wherein R', is as defined in claim 1, their enantiomers and 20 diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
16. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (II') and R represents a group of formula (V), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. S 7>? -96
17. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (II') and R represents a group of formula (VI), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
18. Compounds of formula (I) according to claim 1, wherein A represents a ring system of 5 formula (III') and R represents a group of formula (VII), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
19. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (III') and R represents a group of formula (V), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 10
20. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (III') and R represents a group of formula (VI), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
21. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (III') and R represents a group of formula (VII), their enantiomers and 15 diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
22. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (II') substituted in the 5-position by a group of formula (V) and in the 3-position by a group of formula (IX), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 20
23. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (II') substituted in the 5-position by a group of formula (V) and in the 3-position by a group of formula (IX), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
24. Compounds of formula (I) according to claim 1, wherein A represents a ring system of 25 formula (II') substituted in the 5-position by a group of formula (VII) and in the 3-position - 97 by a group of formula (IX), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
25. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (III') substituted in the 7-position by a group of formula (V) and in the 1- or 2 5 position by a group of formula (IX), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
26. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (III') substituted in the 7-position by a group of formula (VI) and in the 1- or 2 position by a group of formula (IX), their enantiomers and diastereoisomers, and addition 0 salts thereof with a pharmaceutically acceptable acid or base.
27. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (III') substituted in the 7-position by a group of formula (VII) and in the 1- or 2 position by a group of formula (IX), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 15
28. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (II'), which are substituted in the 5-position by a group -CONR'aR", wherein R', and R"a are as defined in claim 1 and substituted in the 3-position by a group of formula (IX) wherein G represents an unsubstituted or substituted chain -(CH 2 )i-, wherein t is 2 or 3, and R represents a group Ra Ra -a-. - ' NC - NR'aR" or C-NR'aR"a wherein Q, Ra, R'a and R"a 20QQQ are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
29. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (II'), which are substituted in the 5-position by a group -SO2NR',R", wherein R'a and 2 R", are as defined in claim 1 - 98 and substituted in the 3-position by a group of formula (IX) wherein G represents an unsubstituted or substituted chain -(CH 2 )-, wherein t is 2 or 3, and R represents a group Ra Ra -N-C-R'a ' -NC - NR'aR"a or - C- NR'aR"a wherein Q, Ra, R'a and R"a I I I I I I Q Q Q are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof 5 with a pharmaceutically acceptable acid or base.
30. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (II') substituted in the 5-position by a group -NHCOR'a wherein R'a is as defined in claim 1 and which are substituted in the 3-position by a group of formula (IX) wherein G represents 0 an unsubstituted or substituted chain -(CH 2 ),-, wherein t is 2 or 3, and R' represents a group Ra Ra -N-C-R'a ' -NC - NR'aR"a or - -NR'aR"a wherein Q, Ra, R'a and R"a I I I I I I Q Q Q are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
31. Compounds of formula (I) according to claim 1, wherein A represents a ring system of 5 formula (II'), which are substituted in the 5-position by a group -NHCOOR'a wherein R' is as defined in claim 1 and substituted in the 3-position by a group of formula (IX) wherein G represents an unsubstituted or substituted chain -(CH 2 ):-, wherein t is 2 or 3, and R represents a group Ra Ra -- C R'a N -C-NR'aR"a or - C-NR'aR"a wherein Q, Ra, R'a and R"a I I I I I I Q Q Q 20 are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. I S -99
32. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (II'), which are substituted in the 5-position by a group COOR'a wherein R'a is as defined in claim 1 and substituted in the 3-position by a group of formula (IX) wherein G represents an 5 unsubstituted or substituted chain -(CH 2 ):-, wherein t is 2 or 3, and R represents a group Ra Ra a -N-C-R'a ' -N-C-NR'aR"a or -C-NR'aR"a wherein Q, Ra, R'a and R"a I I I I I I Q Q Q are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
33. Compounds of formula (I) according to claim 1, wherein A represents a ring system of 0 formula (1IP), which are substituted in the 7-position by a group of formula -CONR'aR"a wherein R'a and R"a are as defined in claim 1 and substituted in the 1- or 2-position by a group of formula (IX) wherein G represents an unsubstituted or substituted chain -(CH 2 )i-, wherein t is 2 or 3, and R' represents a group Ra Ra -N-C-R'a ' N-C-NR'aR"a or C- NR'aR"a wherein Q, Ra, R'a and R"a I I I I I I Q Q Q 5 are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
34. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (III'), which are substituted in the 7-position by a group -SO2NR'aR'a wherein R'a and R"a are as defined in claim 1 20 and substituted in the 1- or 2-position by a group of formula (IX) wherein G represents an unsubstituted or substituted chain -(CH 2 ),-, wherein t is 2 or 3, and R' represents a group Ra Ra a a aa - N -C- R'a -NC -NR'aR"a or C - NR'R"a wherein Q, Ra, R'a and R"a I I I I I I Q Q Q are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. -100
35. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (III'), which are substituted in the 7-position by a group -NHCOR'a wherein R'a is as defined in claim 1 and substituted in the 1- or 2-position by a group of formula (IX) wherein G represents an 5 unsubstituted or substituted chain -(CH 2 )-, wherein t is 2 or 3, and R' represents a group Ra Ra -N-C-R'a ' -N-C-NR'aR"a or -C-NR'aR'a wherein Q, Ra, R'a and R"a Q Q Q are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
36. Compounds of formula (I) according to claim 1, wherein A represents a ring system of 10 formula (III') substituted in the 7-position by a group -NHCOOR'a wherein R'a is as defined in claim 1 and which are substituted in the 1- or 2-position by a group of formula (IX) wherein G represents an unsubstituted or substituted chain -(CH 2 )-, wherein t is 2 or 3, and R' Ra Ra represents group - N -C-R' N - C - NR'aR"a or - C -NR' R", wherein aepaseas agra' Q Q Q 15 Q, Ra, R'a and R"a are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
37. Compounds of formula (I) according to claim 1, wherein A represents a ring system of formula (III') substituted in the 7-position by a group COOR'a wherein R'a is as defined in claim 1 20 and which are substituted in the 1- or 2-position by a group of formula (IX) wherein G represents an unsubstituted or substituted chain -(CH 2 )i-, wherein t is 2 or 3, and R, Ra Ra -p-eR'goN - C NR' R" or - C - NR'aR"a wherein represents a group -- N - a 'a Q Q Q -101 Q, R, R'a and R"a are as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
38. Compounds of formula (I) according to claim 1, wherein A represents a naphthalene, dihydro- or tetrahydro-naphthalene nucleus, which are optionally substituted (in addition to 5 the substituents R and R'), preferably in the 3-position, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
39. Compounds of formula (I) according to claim 1, wherein A represents a benzofuran or dihydrobenzofuran nucleus, which are optionally substituted (in addition to the substituents R and R'), preferably in the 2-position, their enantiomers and diastereoisomers, and addition 10 salts thereof with a pharmaceutically acceptable acid or base.
40. Compounds of formula (I) according to claim 1, wherein A represents a benzothiophene or dihydrobenzothiophene nucleus, which are optionally substituted (in addition to the substituents R and R'), preferably in the 2-position, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 15
41. Compounds of formula (I) according to claim 1, wherein A represents an indole or indoline nucleus, which are optionally substituted (in addition to the substituents R and R'), preferably in the 2-position, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
42. Compounds of formula (I) according to claim 1, wherein A represents an azaindole nucleus 20 optionally substituted (in addition to the substituents R and R'), preferably in the 2-position, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
43. Compounds of formula (I) according to claim 1, wherein A represents a naphthalene, dihydro- or tetrahydro-naphthalene nucleus, which are optionally substituted (in addition to 25 the substituents R and R') in the 3-position, substituted in the 7-position by a group -NHCORa, SO 2 NHRa, COOR'a or CONHRa wherein Ra and Ra are as defined in claim 1, - 102 and substituted in the 1-position by a group -(CH 2 ),-NHCOR'a or -(CH 2 ),-CONHR'a, wherein t is 2 or 3 and R'a is as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
44. Compounds of formula (I) according to claim 1, wherein A represents a benzofuran or 5 dihydrobenzofuran nucleus, which are optionally substituted (in addition to the substituents R and R') in the 2-position, substituted in the 5-position by a group -NHCORa, SO 2 NHRa, COOR'a or CONHRa wherein R. and R'a are as defined in claim 1, and substituted in the 3 position by a group -(CH 2 )tNHCOR'a or -(CH 2 )cCONHR'a, wherein t is 2 or 3 and R'a is as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a 0 pharmaceutically acceptable acid or base.
45. Compounds of formula (I) according to claim 1, wherein A represents a benzothiophene or dihydrobenzothiophene nucleus, which are optionally substituted (in addition to the substituents R and R') in the 2-position, substituted in the 5-position by a group -NHCORa, SO 2 NHRa, COOR'a or CONHRa wherein Ra and RIa are as defined in claim 1, and 15 substituted in the 3-position by a group -(CH 2 )t-NHCOR'a or -(CH 2 ),cCONHR'a, wherein t is 2 or 3 and R'a is as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
46. Compounds of formula (I) according to claim 1, wherein A represents an indole or indoline nucleus, which are optionally substituted (in addition to the substituents R and R') in the 2 20 position, substituted in the 5-position by a group -NHCORa, SO 2 NHRa, COOR'a or CONHRa wherein Ra and R'a are as defined in claim 1, and substituted in the 3-position by a group -(CH 2 )tNHCOR'a or -(CH 2 ),-CONHR'a, wherein t is 2 or 3 and R'a is as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 25
47. Compounds of formula (I) according to claim 1, wherein A represents an azaindole nucleus, which are optionally substituted (in addition to the substituents R and R') in the 2-position, substituted in the 5-position by a group -NHCORa, SO 2 NHRa, COOR'a or CONHRa wherein Ra and R'a are as defined in claim 1, and substituted in the 3-position by a group - 103 -(CH 2 )t-NHCOR'a or -(CH 2 )i-CONHR'a, wherein t is 2 or 3 and R'a is as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
48. Compound of formula (I) according to claim 1, wherein A represents a naphthalene, 5 dihydronaphthalene or tetrahydronaphthalene nucleus, which are optionally substituted (in addition to the substituents R and R') in the 3-position, substituted in the 7-position by a alk group -NHCOORa or -NCOORa wherein Ra is as defined in claim 1 and alk represents an alkyl group, and substituted in the 1-position by a group -(CH 2 )t-NHCOR'a or -(CH 2 ),-CONHR'a, wherein t is 2 or 3 and R'a is as defined in claim 1, their enantiomers and 0 diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
49. Compounds of formula (I) according to claim 1, wherein A represents a benzofuran or dihydrobenzofuran nucleus, which are optionally substituted (in addition to the substituents alk R and R') in the 2-position, substituted in the 5-position by a group -NHCOORa or -N-COORa 5 wherein Ra is as defined in claim 1 and alk represents an alkyl group, and substituted in the 3-position by a group -(CH 2 )-NHCOR'a or -(CH 2 ),-CONHR'a, wherein t is 2 or 3 and R'a is as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
50. Compounds of formula (I) according to claim 1, wherein A represents a benzothiophene or 20 dihydrobenzothiophene nucleus, which are optionally substituted (in addition to the substituents R and R') in the 2-position, substituted in the 5-position by a group alk -NHCOORa or -NCOORa , wherein Ra is as defined in claim I and alk represents an alkyl group, and substituted in the 3-position by a group -(CH 2 )t-NHCOR'a or -(CH 2 ),-CONHR'a, wherein t is 2 or 3 and Ra is as defined in claim 1, their enantiomers and 25 diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. -104
51. Compounds of formula (I) according to claim 1, wherein A represents an indole or indoline nucleus, which are optionally substituted (in addition to the substituents R and R') in the alk 2-position, substituted in the 5-position by a group -NHCOORa or -NCOORa wherein Ra is as defined in claim 1 and alk represents an alkyl group, and substituted in the 5 3-position by a group -(CH 2 )-NHCOR'a or -(CH 2 )-CONHR'a, wherein t is 2 or 3 and R'a is as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
52. Compounds of formula (I) according to claim 1, wherein A represents an azaindole nucleus, which are optionally substituted (in addition to the substituents R and R') in the 2-position, alk substituted in the 5-position by a group -NHCOORa or -NCOORa , wherein Ra is as [0 defined in claim 1 and alk represents an alkyl group, and substituted in the 3-position by a group -(CH 2 )t-NHCOR'a or -(CH 2 ),-CONHR'a, wherein t is 2 or 3 and R'a is as defined in claim 1, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 15
53. Compound of formula (I) according to claim 1 that is N-{2-[6-(acetylamino)-2,3-dihydro 1H-1-indenyl]ethyl}acetamide, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
54. Compounds of formula (I) according to claim 1 that are: * methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate, 20 * methyl 3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate, * methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate, * methyl 3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate, * methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate, * methyl 3-[2-(isobutylamino)ethyl]-1-benzofuran-5-carboxylate, 25 their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 7% - 105
55. Compounds of formula (I) according to claim 1 that are: * N,N-diphenyl-3-[3-(acetylamino)propyl]benzo[b]furan-5-carboxamide, * 3-[2-(acetylamino)ethyl]-1-benzofuran-5-carboxamide, * 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxamide, 5 * 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxamide, * 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide, * 3-[2-(acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide, * 3-{2-[(cyclopentylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide, * 3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide, [0 * 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-ethyl-i-benzofuran-5-carboxamide, * 3-[2-(benzoylamino)ethyl]-N-ethyl-1-benzofuran-5-carboxamide, * 3-[2-(acetylamino)ethyl]-N-methyl-1H-pyrrolo[ 2 ,3-b]pyridine-5-carboxamide, * N-isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b]thiophene 5-carboxamide, 15 * 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxamide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
56. Compounds of formula (I) according to claim 1 that are: * N-{3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide, 0 * N-{2-[5-(acetylamino)-1-benzofuran-3-yl]ethyl}cyclopropanecarboxamide, * N-{2-[5-(acetylamino)-1-benzothiophen-3-yl]ethyl}benzamide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
57. Compounds of formula (I) according to claim 1 that are: 25 * N-{8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}butanamide, * N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)-1-cyclohexanecarboxamide, * N-{8-[2-(heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide, * N-{8-[2-(acetylamino)ethyl]-2-naphthyl}acetamide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically 30 acceptable acid or base. -106
58. Compounds of formula (I) according to claim 1 that are: * N-ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide, * NN-diethyl-8-{2-[2-[(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide, * N-phenyl-8-(2-{methyl[(propylamino)carbonyl]amino}ethyl)-2-naphthamide, 5 * N-benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide, * N-(2-{7-[(methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
59. Compounds of formula (I) according to claim 1 that are: 0 * N-{2-[7-(aminosulphonyl)-1-naphthyl]ethyl}acetamide, * N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide, * N-(2- {7-[(methylamino)sulphonyl]- 1 -naphthyl} ethyl)-2-furamide, * N-(2-{7-[(ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide, * N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethylcyclopropanecarboxanide, 5 their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
60. Compounds of formula (I) according to claim 1 that are: * N-(3-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}propyl)acetamide, * N-(2-{5-[(propylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)acetamide, 20 * N-(2- {5-[(cyclopropylamino)sulphonyl]- 1 -benzofuran-3-yl } ethyl)benzamide, * N-(2- {5-[(methylamino)sulphonyl]- I -benzofuran-3-yl} ethyl)-2-furamide, * N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropanecarboxamide, * N-(2-{2-benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)acetamide, * N-(2-{5-[(isopropylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)cyclopropane 25 carboxamide, * N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[ 2 ,3-b]pyridin-3-yl}ethyl)acetamide, * N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[ 2 ,3-b]pyridin-3-yl}ethyl)cyclopropane carboxamide, * N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[ 2 ,3-b]pyridin-3-yl}ethyl)benzamide, - 107 * N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[ 2 ,3-b]pyridin-3-yl}ethyl)-2-furamide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
61. Compounds of formula (I) according to claim 1 that are: 5 * methyl N-{3-[2-(acetylamino)ethyl]benzo[b]furan-5-yl}carbamate, * methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate, * tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate, * tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate, * methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate, 0 * methyl 3-[2-(isobutyrylamino)ethyl]- 1 -benzofuran-5-yl-carbamate, * methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate, * methyl 3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. .5
62. Compound of formula (I) according to claim 1 that is methyl 5-[(acetylamino)methyl]-2,3 dihydro-1,4-benzodioxin-6-yl-carbamate, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
63. Compound of formula (I) according to claim 1 that is methyl 3-[(acetylamino)methyl]-3,4 dihydro-2H-chromen-6-yl-carbamate, its enantiomers and diastereoisomers, and addition 20 salts thereof with a pharmaceutically acceptable acid or base.
64. Compound of formula (I) according to claim 1 that is ethyl 3-[2-(acetylamino)ethyl]-2,3 dihydro-1H-inden-5-yl-carbamate, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
65. Compounds of formula (I) according to claim 1 that are: 25 * methyl 3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate, * methyl 3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate, 'U s * methyl 3-[2-(benzoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate, - 108 * methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[ 2 ,3-b]pyridin-5-yl carbamate, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 5
66. Compounds of formula (I) according to claim 1 that are: * ethyl N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate, * methyl N-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate, * hexyl N-{8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}carbamate, * methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically 0 acceptable acid or base.
67. Process for the preparation of compounds of formula (I), characterised in that there is used as starting material the compound of formula (X) : H 3 C-0, (X) A - R' wherein A and R' are as defined hereinbefore, which is subjected to demethylation using 5 conventional agents such as HBr, AlCl 3 , AlBr 3 , BBr 3 or Lewis acid/nucleophile binary systems such as AlCl 3 /PhCH 2 SH, or BBr 3 /Me 2 S, for example, to obtain the compound of formula (XI): HO-A-R' (XI) wherein A and R' are as defined hereinbefore, + which is converted, by means of the action of reagents such as POCl 3 , PCl, Ph 3 PBr 2 , PhPCl 4 , 20 HBr or HI, into the corresponding halogenated compound of formula (XII): Hal-A-R' (XII) wherein A and R' are as defined hereinbefore and Hal represents a halogen atom (which compounds of formula (XII) can be obtained by exchange reactions such as, for example, the treatment of a chlorinated compound with KF in dimethylformamide to yield the corresponding -109 fluorinated compound or the treatment of a brominated compound with KI in the presence of copper salts to yield the corresponding iodinated compound), which is treated: with carbon monoxide and Bu 3 SnH, the reaction being catalysed with palladium(O), to yield the 5 corresponding aldehyde of formula (XIII): H-C-A-R' (XIII) II 0 wherein A and R' are as defined hereinbefore, which compound of formula (XIII) may alternatively be obtained by customary lithiation methods starting from the halogenated compound of formula (XII), or via the corresponding 10 vinyl compound (obtained starting from the compound of formula (XII) by the action of vinyltributyltin and tetrakis palladium) subjected to ozonolysis, or furthermore by direct formylation of the nucleus A, for example according to a Vilsmeier reaction, which compound of formula (XIII) is subjected to an oxidising agent to obtain the compound of formula (XIV) : 15 HOOC - A -R' (XIV) wherein A and R' are as defined hereinbefore, which is: * either subjected, in the presence of an acid catalyst, to the action of an alcohol of formula R'aOH, wherein R'a is as defined hereinbefore, to yield the compound of formula (I/a), a 20 particular case of the compounds of formula (I): R - - C - A - R' (I/a) a A I 0 wherein A, R'a and R! are as defined hereinbefore, Th -110 which may be subjected to a thionating agent, such as Lawesson's reagent, for example, to yield the compound of formula (I/b), a particular case of the compounds of formula (I): R'a - O - C - A - R' (I/b) aI I S wherein A, R'a and R' are as defined hereinbefore, 5 * or converted, after the action of thionyl chloride and an azide, and then of an acid, into the compound of formula (XV): H 2 N-A-R' (XV) wherein A and R' are as defined hereinbefore, with which there is condensed: - either an acyl chloride C1CORa or the corresponding anhydride (mixed or symmetrical), 0 wherein Ra is as defined hereinbefore, to yield the compound of formula (I/c), a particular case of the compounds of formula (I): Ra- C-NH- A-R' (I/c) I I 0 wherein Ra, A and R' are as defined hereinbefore, which may be subjected to the action of a compound of formula (XVI): R I-J (XVI) 15 wherein R'a is as defined hereinbefore and J represents a leaving group such as a halogen atom or a tosyl group, to obtain the compound of formula (I/d), a particular case of the compounds of formula (I): -111 R Ia R -C-N-A-R' (I/d) 11 0 wherein Ra, R., A and R' are as defined hereinbefore, which compounds of formulae (I/c) and (I/d) constitute the compound of formula (I/e), a particular case of the compounds of formula (I) R'A Ra - C -N -A- R! (I/c) II 5 0 5 wherein Ra, R'a, A and R' are as defined hereinbefore, which compound of formula (I/e) may be subjected to a thionating agent, such as Lawesson's reagent, for example, to obtain the compound of formula (I/f), a particular case of the compounds of formula (I): R' I a R -C N-- A - R'! II S 10 wherein Ra, R'a, A and R' are as defined hereinbefore, - or a compound of formula (XVII): Q=C=N-R'a (XVII) wherein Q and R'a are as defined hereinbefore, 15 to yield the compound of formula (I/g), a particular case of the compounds of formula (I): ANS -112 R'aNHC-NH-A-R' (h/g) || Q wherein R'a, Q, A and R' are as defined hereinbefore, which may be subjected to the action of a compound of formula (XVI) to obtain the compound of formula (I/h), a particular case of the compounds of formula (I): R' RR'N-CN- A - R' (I/h) I I 5 Q wherein Q, R'a, A and R' are as defined hereinbefore and R 2 . and R' 2 a, which may be the same or different, may take any of the values of Ra except for the hydrogen atom and cannot form a cyclic structure together with the nitrogen atom carrying them, - or a compound of formula (XVIII): R'a -o-c-Ci (XVIII) 00 0 wherein R'a is as defined hereinbefore, or its corresponding anhydride (R'aOCO) 2 0, to obtain the compound of formula (I/i), a particular case of the compounds of formula (I): R'aOC -NH- A -R' (/) I1 0 wherein R'a, A et R' are as defined hereinbefore, 5 which may be subjected to the action of a compound of formula (XVI) and/or the action of a thionating agent to yield the compound of formula (I/j), a particular case of the compounds of formula (I): US - 113 Ra Il Q wherein Ra, R'a, Q, A and R' are as defined hereinbefore, - or a compound of formula (XIX): RaSO 2 Cl (XIX) 5 wherein Ra is as defined hereinbefore, optionally followed by the action of a compound of formula (XVI) to yield the compound of formula (I/k), a particular case of the compounds of formula (I): R' I a RaSO--N-A-R' (I/k) 10 wherein Ra, A and R' are as defined hereinbefore, + or which compound of formula (XI) is converted, by means of the action of benzylthiol and trifluoromethanesulphonic acid, into the corresponding benzylthio compound of formula (XX) : Ph-CH 2 -S-A-R' (XX) 15 wherein A and R' are as defined hereinbefore, which is placed in the presence of iodosobenzene and hydrochloric acid to yield the compound of formula (XXI) : ClSO 2 -A-R' (XXI) wherein A and R' are as defined hereinbefore, 20 with which there is condensed an amine R'aR"aNH (wherein R'a and R"a are as defined hereinbefore), -114 to obtain the compound of formula (Il), a particular case of the compounds of formula (I): R'aR"aNSO 2 -A-' (I/l) wherein R'a, R"a, A and R' are as defined hereinbefore, it being possible for the compound of formula (I/la), a particular case of the compounds of 5 formula (I/l): H 2 NSO 2 -A-R' (I/la) wherein A and R' are as defined hereinbefore, to be subjected to the action * of an acyl chloride ClCOR'a, optionally followed by the action of a compound of formula (XVI) and/or Lawesson's reagent, 10 to yield the compound of formula (I/m), a particular case of the compounds of formula (I): R Ia R'aC-N-SOF-A-R' (I/m) l Q wherein Ra, R'a, Q, A and R' are as defined hereinbefore, * of a compound of formula (XVII), optionally followed by the action of a compound of formula (XVI) to obtain the compound of formula (I/n), a particular case of the compounds of formula (I): Ra I a R'aRaN-C-N-SOF-A-R' (I/n) 11 15 Q wherein Ra, Wa, R"a, Q, A and R' are as defined hereinbefore, e or of a compound of formula (XVIII), optionally followed by the action of a compound of formula (XVI), - 115 to yield the compound of formula (I/o), a particular case of the compounds of formula (I): R I a R'aOC-N-SOi-A-R' (I/o) II 0 wherein Ra, R'a, A and R' are as defined hereinbefore, which compounds (I/a) to (I/o) can be purified in accordance with a conventional separation 5 technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and, optionally, are separated into their isomers in accordance with a conventional separation technique.
68. Process for the preparation of compounds of formula (I), characterised in that there is used as starting material the compound of formula (XII): R 0 Y"1 (XXII) 10 wherein R and the symbol ... are as defined hereinbefore, Y" represents a group C(H)q (wherein q is 0, 1 or 2) or a bond, and X" represents an oxygen, nitrogen or sulphur atom or a group C(H)q (wherein q is 0, 1 or 2) or NRO (wherein R 0 is as defined hereinbefore), it being understood that when X" represents a nitrogen atom or a group NRO then Y" represents a bond, 15 which is subjected to a Wittig reaction and then to reduction to yield the compound of formula (XXIII): R G-CN (XXIII) wherein R, X", Y", G and the symbol .are as defined hereinbefore, -116 which may be oxidised to yield the compound of formula (XXIV): R G-CN (XXIV) wherein R', X", Y", G and the symbol .are as defined hereinbefore, which is: 5 * either hydrolysed in an acid or basic medium and then subjected, after activation to the acid chloride form or in the presence of a coupling agent, to the action of an amine HNR'aR"a wherein R'a and R"a are as defined hereinbefore to yield the compound of formula (I/p), a particular case of the compounds of formula (I): 0 R G NR'aR"a (I/p) X, 0 wherein R, X", Y", G, R'a, R"a and the symbol .are as defined hereinbefore, which may be subjected to a thionating agent such as Lawesson's reagent to yield the compound of formula (I/q), a particular case of the compounds of formula (I): S R G NR'aR"a (I/q) wherein R, X", Y", G, R'a, R"a and the symbol .are as defined hereinbefore, isr -117 * or hydrolysed in an acid or basic medium and then converted into the corresponding azide to yield, after having been subjected to a Curtius rearrangement and hydrolysis, the compound of formula (XXV): R G-NH 2 Y1" (XXV) 5 wherein R, X", Y" and G are as defined hereinbefore, which is reacted with: - an acyl chloride ClCOR'a or the corresponding anhydride (mixed or symmetrical) wherein R'a is as defined hereinbefore, optionally followed by the action of a compound of 10 formula (XVI) and/or the action of a thionating agent to yield the compound of formula (I/r), a particular case of the compounds of formula (I): R I a G-N-C-R' R a S(I/r) wherein R, X", Y", G, Ra, R'a, Q and the symbol .. are as defined hereinbefore, - or with a compound of formula (XVII), optionally followed by the action of a compound 15 of formula (XVI) to yield the compound of formula (I/s), a particular case of the compounds of formula (I): R G-N-C-NR'aR"a R 11 (I/s) wherein R, X", Y", G, Ra, R'a, R"a, Q and the symbol .. are as defined hereinbefore, -118 which compounds (I/p) to (I/s) can be purified in accordance with a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and, optionally, are separated into their isomers in accordance with a conventional separation technique. 5
69. Process for the preparation of compounds of formula (I) according to claim 1 wherein R represents a ring of formula (VIII) as defined in claim 1, characterised in that compounds of formulae (I/a) to (I/s) are used as starting materials, which are cyclised according to described conventional methods. Er
70. Pharmaceutical compositions comprising compounds of formula (I) according to any one of 10 claims 1 to 66 or an addition salt thereof with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients.
71. Pharmaceutical compositions according to claim 70 for use in the manufacture of medicaments for the treatment of disorders associated with the melatoninergic system. S7
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